Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2013 / Article
Special Issue

Bioactives and Traditional Herbal Medicine for the Treatment of Cardiovascular/Cerebrovascular Diseases

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Review Article | Open Access

Volume 2013 |Article ID 925625 | https://doi.org/10.1155/2013/925625

Qing Liu, Jiqiang Li, Jing Wang, Jianping Li, Joseph S. Janicki, Daping Fan, "Effects and Mechanisms of Chinese Herbal Medicine in Ameliorating Myocardial Ischemia-Reperfusion Injury", Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 925625, 14 pages, 2013. https://doi.org/10.1155/2013/925625

Effects and Mechanisms of Chinese Herbal Medicine in Ameliorating Myocardial Ischemia-Reperfusion Injury

Academic Editor: Joen-Rong Sheu
Received24 Jul 2013
Revised26 Aug 2013
Accepted04 Sep 2013
Published31 Oct 2013

Abstract

Myocardial ischemia-reperfusion (MIR) injury is a major contributor to the morbidity and mortality associated with coronary artery disease, which accounts for approximately 450,000 deaths a year in the United States alone. Chinese herbal medicine, especially combined herbal formulations, has been widely used in traditional Chinese medicine for the treatment of myocardial infarction for hundreds of years. While the efficacy of Chinese herbal medicine is well documented, the underlying molecular mechanisms remain elusive. In this review, we highlight recent studies which are focused on elucidating the cellular and molecular mechanisms using extracted compounds, single herbs, or herbal formulations in experimental settings. These studies represent recent efforts to bridge the gap between the enigma of ancient Chinese herbal medicine and the concepts of modern cell and molecular biology in the treatment of myocardial infarction.

1. Introduction

Myocardial infarction (MI) and the accompanying acute loss of viable myocardium is the leading cause of death in industrialized countries. Even if the patient survives the acute phase of MI, the subsequent adverse myocardial remodeling and impairment of cardiac function severely impact their quality of life and 5-year survival. Early restoration of blood flow to the ischemic myocardium is a common treatment strategy aimed at limiting myocardial infarct size. However, reperfusion can cause additional cell death and, in many cases, paradoxically increase infarct size, a situation referred to as myocardial ischemia-reperfusion (MIR) injury. MIR is characterized by a rapid increase in cytokines and chemokines and an influx of leukocytes into the vulnerable region bordering the infarcted site. This inflammatory response not only results in cardiomyocyte apoptosis during the acute phase, but also results in an adverse myocardial remodeling that further compromises cardiac function. Therefore, limiting ischemia-reperfusion (I/R) induced myocardial inflammation may not only lower the acute death rate, but also improve long term survival and quality of life [1]. Chinese herbal medicine, especially combined herbal formulations, has been widely used in traditional Chinese medicine for the treatment of MI for hundreds of years. The purpose of this review is to highlight recent studies that experimentally address the mechanistic effects of extracted compounds, single herbs, or herbal formulations on several factors and pathways known to be involved in MIR injury.

2. Myocardial Ischemia-Reperfusion Injury

2.1. Oxidative Stress

Reactive oxygen species (ROS) have both a physiological and pathological role in cellular and tissue adaptation to environmental factors. Normally, low levels of oxygen radicals and oxidants are present in cells and are important in maintaining cellular homeostasis, mitosis, differentiation, and signaling [2]. However, during MIR, ROS formation is markedly increased and cellular injury occurs (Figure 1). Although mammalian cells express endogenous free radical scavenging enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), these antioxidative defenses are insufficient during MIR [3, 4]. Oxidative stress during MIR injury contributes to a vicious cycle as it promotes mitochondrial dysfunction, excitotoxicity, lipid peroxidation, and inflammation [57].

2.2. Sterile Inflammation

Ischemia and reperfusion cause sterile inflammation. Nevertheless, the consequences of MIR share many phenotypic parallels with activation of a host immune response directed toward invading microorganisms [8]. This sterile inflammation is mainly triggered by the interactions between toll-like receptors (TLRs) and their endogenous ligands generated in ischemic and reperfused myocardium, such as apoptotic cell debris, fibrinogen, high mobility group box (HMGB) 1, and heat shock proteins (HSPs) [9]. The activation of immune cell and cardiomyocyte TLR and other signaling pathways results in a vicious cycle of inflammatory response in the I/R region and causes significant cardiomyocyte apoptosis (Figure 1). Following the acute I/R period, the cardiac function is further compromised by adverse myocardial remodeling [10]. The magnitude of the inflammation during the acute phase determines the extent to which cardiac function is compromised during the following myocardial remodeling phase.

During the sterile inflammation phase of MIR, TLRs play detrimental roles as demonstrated by extensive experimental evidence [11]. To date, 11 TLRs (TLR1–TLR11) have been identified in mammals. It should be noted that, during MIR, the expression of TLR4 is significantly increased in both the failing myocardium, and infiltrated macrophages and thus TLR4 is thought to be a central mediator of inflammation and cardiac injury. TLR4 has been identified as a mediator of inflammation and organ injury in several models of sterile tissue injury including MIR, and a soluble inhibitor of TLR4 was able to prevent contractile dysfunction in wild-type cells [12]. Using a temporary left anterior descending (LAD) artery occlusion model, Oyama et al. first observed myocardial infarct size reductions in 2 distinct strains of mice that lack functional TLR4 signaling, accompanied with reduced neutrophil infiltration in the affected myocardium [13]. TLR2, which is expressed in cardiomyocytes and many other cell types, also contributes to the pathogenesis of cardiac dysfunction during MIR [14, 15]. Activation of TLR2, TLR4, and TLR5 increases the myocardial level of the inflammatory cytokines, chemokines, and cell surface adhesion molecules [16]. Given the known role of TLR4 and TLR2 in MIR, inhibition of TLR4 and TLR2 signaling is a promising approach to reduce morbidity and mortality in MI patients.

There are a variety of TLR ligands generated during MIR. For example, heat shock proteins (HSPs) are a class of molecular chaperones that promote intracellular protein folding. They may be released into the extracellular space after cell trauma and interact with adjacent cells or distant cells via bloodstream delivery [17]. Extracellular HSP60 induced apoptotosis via the activation of TLRs [18]. Another example is HMGB1 which is a damage-associated molecular pattern (DAMP) protein secreted by injured cells [19]. It plays a major role in early MIR by binding to TLRs and the receptor for advanced glycation end products (RAGE), resulting in the activation of proinflammatory pathways and enhanced myocardial injury [20]. In fact, a prerequisite for neutrophil-mediated tissue damage is the “priming” effect of various pro-inflammatory stimuli generated by damaged tissue during MIR, such as HSP60 and HMGB1 [21]. Cytokines released by TLR-activated cells such as tumor necrosis factor-alpha (TNF-α) and IL-1 can elicit neutrophil polarization and upregulation of cell-surface glycoproteins such as macrophage adhesion molecule-1 (Mac-1) [22]; Mac-1 upregulation in peripheral neutrophils is a very early event in MIR [23].

2.3. Apoptosis and Mitochondrial Function

MIR leads to the activation of cell death programs, including apoptosis, autophagy-associated cell death, and necrosis [24]. Apoptosis involves an orchestrated caspase signaling cascade, including caspase-3 and caspase-9, which induces a self-contained program of cell death, characterized by the shrinkage of the cell and its nucleus, with plasma membrane integrity persisting until late in the process [25]. The balance between apoptotic factors Bcl-2 and Bax has been found altered in cardiomyocytes during ischemia [26]. Autophagy is stimulated by nutrient starvation and growth factor deprivation when cells are unable to take up external nutrients. Autophagy is also activated by decreases in ATP in order for the cell to maintain energy homeostasis and survival. Autophagy may serve primarily to maintain energy production during acute ischemia but switch to clear up damaged organelles during chronic ischemia or reperfusion [27].

Multiple cell signaling pathways, such as the AMPK, JNK, and NF-κB pathways, have been shown to be involved in MIR-induced cardiomyocyte apoptosis (Figure 1). AMPK orchestrates the regulation of energy-generating and energy-consuming pathways; its activation has been shown to protect the heart against ischemic injury [28, 29]. Activated JNK signaling, especially in mitochondria, is associated with oxidative stress, mitochondrial dysfunction, and cell death [30]; it is a key modulation event in cell death mediated by reactive oxygen and nitrogen species [31]. JNK is also required for TNF-α-stimulated ROS production and cytochrome c-mediated cell death; Bcl-2 family members are essential components of this mitochondrial apoptotic machinery. Studies have suggested that blockage of JNK mitochondrial translocation or JNK inhibition prevents ROS production and mitochondrial dysfunction and may be an effective treatment for I/R-induced cardiomyocyte death [3235]. The nuclear factor kappa B (NF-κB) also modulates apoptosis during ischemia and reperfusion [36]. TLR signaling pathway leads to translocation of NF-κB to the nucleus and thus up-regulation of expression of proinflammatory cytokines. However, there is the possibility that a crosstalk between the TLR/NF-κB and PI3K/Akt signaling pathways and modulation of the crosstalk could protect the myocardium from I/R injury [37].

Within the mitochondria dependent intrinsic apoptosis pathway, which has an important function in cardiac cell injury under various pathological conditions [38], mitochondrial permeability transition pore (MPTP) opening plays a pivotal role [39]. The event of MPTP opening is affected by various factors including intracellular Ca2+, oxidative radicals, ATP levels and the levels of Bcl-2 family proteins [40].

2.4. Bone Marrow Stem Cell Migration

Bone marrow mesenchymal stem cells (BMSCs) are multipotent cells that secrete angiogenic factors. Injured tissues express specific receptors, such as CXCR4, and/or their ligands including stromal cell-derived factor-1 (SDF-1), to facilitate trafficking, adhesion, and infiltration of BMSCs. During MIR, BMSCs are preferentially attracted to and retained in the ischemic tissue [41, 42]. As a result of the hypoxic microenvironment, these BMSCs produce high levels of vascular endothelial growth factor (VEGF), leading to an increase in vessel density and facilitating myocardial regeneration and remodeling [43, 44] (Figure 1).

2.5. Angiogenesis

Angiogenesis refers to the sprouting, bridging, intussusception, and/or enlargement of capillaries. In the late stage of MI repair, enhancement of blood flow to ischemic myocardium can result from either true angiogenesis or the recruitment of preexisting coronary collaterals [45]. VEGF is an endothelial cell-specific angiogenic factor and also a critical regulator of angiogenesis that stimulates proliferation, migration, and proteolytic activity of endothelial cells [46]. Ischemia or coronary artery occlusion induces myocardial VEGF expression, which leads to an angiogenesis-induced restoration of tissue blood flow and the prevention of further tissue damage (Figure 1). In addition, VEGF is a potent survival factor during physiological and tumor angiogenesis, and has been shown to induce expression of anti-apoptotic proteins in endothelial cells [47, 48].

2.6. Other Factors

The activation of ATP-sensitive potassium (KATP) channel subunits and ATPase, and calcium (Ca2+) overload are also involved in MIR (Figure 1). Ischemia-reperfusion may activate some ion channels that do not open under normal physiological conditions. One such channel is the KATP channel, whose activation facilitates potassium ion efflux, hyperpolarization, and action potential repolarization. The resulting shortening of the action potential duration decreases the total influx of sodium and calcium, which alleviates overloading of intracellular calcium (Ca2+) which in turn weakens myocardial contraction force and reduces myocardial oxygen consumption. Therefore, the opening of KATP channels plays an active role in protecting the heart against MIR injury.

3. Effects and Mechanisms of Chinese Herbal Medicine in MIR

The typical symptoms of cardiovascular diseases induced by MIR have been recorded in several ancient books of Traditional Chinese Medicine (TCM), such as Inner Canon of Huangdi and Treatise on Febrile Diseases. In TCM, Qi (energy) and Blood (material) are the main components compromised in MIR, whereby the principal mechanism is considered to be a disorder or deficiency of Qi and a disorder of the circulation (blood stasis) that results in severe pain and even death. Therefore, the main aims of Chinese herbs and herbal formulations in MIR treatment are to regulate or replenish Qi, and to unblock circulation or resolve blood stasis. In Tables 14, we list four categories of Chinese herbal medicine that have been used in the practice of TCM and/or recent research, including compounds extracted from herbs (Table 1), single herbs (Table 2), decoctions (Table 3), and patent drugs made up of Chinese herbs (Table 4). All of the abbreviations used in these tables are listed at the end of the paper, and the main mechanisms and the representatives of Chinese herbal medicine in MIR treatment are schematized in Figure 1. In the following sections, these herbal medicines are grouped according to their efficacy in TCM terminology, and the underlying cellular and molecular mechanisms demonstrated by experimental investigations are discussed.


Mechanism of action in TCM terminologyPlantCompoundMechanismBiomarker/TargetsIn vivo/In vitroReferences

Tonifying Qi (energy) to activate circulation and enrich Blood Salvia miltiorrhiza Tanshinone IIAAnti-inflammationMCP-1, TGF-β1, TNF-α, NF-κBIn vivo[56]
AntioxidantVEGF, HIF-1 ; MDA, SOD, GPxBoth[68, 72]
AntiapoptosisBcl-2/Bax, caspase-3Both[72]
Promote angiogenesisVEGF, HIF-1 In vivo[68]
Promote BMSCs migrationSCF-1, CXCR-4In vivo[67]
Sodium tanshinone IIA sulfonateAnti-apoptosisLDH, JNK, p38In vivo[73]
Magnesium tanshinoate BAnti-apoptosisp-JNK, cytochrome c, caspase-3In vitro [74]
Salvianolic acid AActivate calcium channels I-CaLIn vivo [75]
Salvianolic acid BPromote angiogenesisVEGFIn vivo[76]
Salvianolic acidsAntioxidant15-F2t-IsoP, ET-1, CK-MBIn vivo[77]
Reduce MECKIn vitro[78]
Tanshinone combined with salvianolic acidsInhibit of intracellular calcium, and anti-apoptosis, antioxidantsICAM-1, Ca2+In vivo[79]
Tanshinone IIA combined with salvianolic acid BAntioxidantCAT, L-arginine, eNOS, AMPK, AktIn vivo[80]
DanshensuAntioxidant, reduce MESOD, MDA; CKMB, LDHIn vivo[81]
Salvia miltiorrhiza extractAntioxidant, reduce MEMDA, SOD, and GPx; LDH, CK, GOTIn vivo[82, 83]
Aqueous extracts of Salvia miltiorrhizae Reduce ME, promote angiogenesisCK-MB and cTnT, 6-keto-PGF-1 /TXB-2In vivo[84]
Salvia miltiorrhizae AntioxidantCOX-2; TXB2, 6-keto-PGF1- In vivo[85]
Radix Ginseng Saponin of red ginsengInhibit Ca2+ overload, up-regulate KATPCa2+; KATP; cTnI; PI3KBoth[86, 87]
Total ginsenosidesAntioxidant, anti-apoptosisCa2+; eNOS, iNOS, GR; PI3K, AktIn vivo[87, 88]
Radix Ginseng extractsAntioxidant, reduce MENO, eNOS; CK, LDHIn vivo[88]
Astragalus membranaceus Astragaloside IVUp-regulate KATP channel subunits, facilitate KATP currentsKATP channel subunits Kir6.1, Kir6.2, SUR2A, SUR2BIn vivo[70]
Rhodiola Salidroside, tyrosolAnti-apoptosiscaspase-3, p-JNK, cytochrome cIn vitro[60]
Millettia pulchra 17-Methoxyl-7-hydroxy-benzene-furanchalconeAntioxidant, anti-inflammation, and anti-apoptosisMDA; TNF-α; NF-κB p65, Bcl-2-associated X proteinBoth[89]
Schisandra chinensis Schisandrin BAnti-inflammation and Hsp25, Hsp70In vivo[57]
Antioxidantcytochrome P-450In vivo [90]
Lycium barbarum Lycium barbarum polysaccharidesIncrease Na+-K+-ATPase and Ca2+-ATPase, anti-apoptosisNa+-K+-ATPase, Ca2+-ATPase; Bax, Bcl-2In vivo[71]

Moving Qi and activating circulation to resolve stasisLigusticum wallichii TetramethylpyrazineAntioxidant, inhibit neutrophilHO-1; Migrated neutrophilIn vivo[91]
Aqueous extracts of Rhizoma ChuanxiongReduce ME, promote angiogenesisCK-MB, cTnT; 6-keto-PGF-1 /TXB-2In vivo[84]
Carthamus tinctorius L.Extracts of Carthamus tinctorius Antioxidant, anti-inflammationROS, MDA, SOD; CRP, TNF- , IL-1 ; PI3KBoth[92, 93]
Panax notoginseng Extracts of Panax notoginseng Antioxidant, anti-inflammationMDA, SOD; CRP, TNF- , IL-1 In vivo[92]
NotoginsengnosidesReduce MECKIn vitro[78]
Dipsacus asper Asperosaponin VIAntioxidant, reduce ME, and protect mitochondrial functionSOD, GOT, GPx, MDA; CK-MB, LDH, cTnT; ICDH, MDH, -KGDH, ATP, Ca2+In vivo[94]
Anti-apoptosis, reduce MEBcl2/Bax, caspase-3; LDH, CREB, PI3KIn vitro[95]
Pyrolae Flavonoid of Herba PyrolaeAntioxidant, reduce MESOD, MDA; CK, LDHIn vivo[96]
Lamiophlomis rotata Forsythoside BAntioxidant, anti-inflammationMDA, MPO, SOD, GPx;Tn-T, TNF- , IL-6, HMGB1; IkBa, NF-κBIn vivo[50]
Sida cordifolia L.Hydroalcoholic extract of Sida cordifolia L.Antioxidant, reduce MESOD, CAT; LDH, CK-MBIn vivo[24]
Desmodium Desmodium gangeticumStimulate muscarinic receptorsMuscarinic receptorIn vivo[97]

Inducing Diuresis to resolve stasisLeonurus 3,5-Dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid
4-Guanidino-butyl ester
Anti-apoptosisCaspase-3, Bcl-2/Bax, AktIn vitro[61]
4-Guanidino-n-butyl syringateInhibit Ca2+ overload, antiapoptosisCa2+; Bcl-2, Bax, LDHIn vivo[98]
Acorus gramineus Acori graminei Rhizoma Inhibit calcium overloadCa2+In vivo[99]
Phytolacca Oleanolic AcidAnti-apoptosisAMPK, p38, FOXO3In vitro[100]
Tetrandra TetrandrineInhibit neutrophil, antioxidantneutrophil adhesion, Mac-1; ROSIn vivo[23]

Cooling Blood to stop bleedingBaicalensis Botanical FlavonoidsAntioxidantROS, NO, SOD, CAT, GPxBoth[101, 102]
Coptidis rhizoma PalmatineAntioxidant, reduce MESOD, MDA, COX-2; LDH, CKIn vivo[49]
Buxus microphylla Cyclovirobuxine DAntioxidant, reduce MEKATP channel opening; NO, ROS, SOD, MDA; CPK, LDH, FFAIn vivo[52, 103]

Tonifying Qi to invigorate Yang Cinnamon 2-MethoxycinnamaldehydeAntioxidant, anti-inflammationVCAM-1,TNF- , HO-1In vivo[51]
Herba Cistanches A semipurified fraction of Herba CistanchesProtect mitochondrial function, antioxidant, and anti-apoptosisATP-generation, mitochondrial uncoupling; GSH; caspase-3Both[65]

Regulating Qi and moving Qi Corydalis Corydalis yanhusuo extractAnti-apoptosisBax, Bcl-2In vivo[104]
Magnolia officinalis MagnololAntioxidant; inhibit neutrophilMPO, superoxide anion; migrated neutrophilIn vivo[105]


Mechanism of action in TCM terminologyHerbMechanismBiomarker/TargetsIn vivo/In vitroReferences

Replenishing and moving Qi Rhodiola Promote angiogenesisVEGFR (Flt-1, KDR, and Tie-2)In vivo[106]
Euryale ferox (Makhana) AntioxidantTRP32, ROS, and Trx-1Both[53]
Aurantii Fructus Recovery of contractile dysfunctionPerfusion pressure, aortic flow, and coronary flowIn vivo[107]


Mechanism of action in TCM terminologyDecoctionConstituent herbsMechanismBiomarker/TargetsIn vivo/In vitroReferences

Tonifying Qi to enrich Blood DangGui BuXue Decoction Astragali and Angelica rootsAntioxidant, protect mitochondrial functionGSH, GSSG, GRDIn vivo [108]
BuYang HuanWu Decoction Astragalus, angelica, red peony, earthworm, and so forthReduce ME LDH, CK, AST; CD40-CD40LIn vivo[109]

Replenishing Qi to activate Blood and recover circulationShuMai Decoction Astragalus mongholicus, Salvia miltiorrhiza, Eupolyphaga,
Wallich and Hirudo nipponica Whitman, Moschus berezovskii
Anti-inflammationTNF-α, p38, MAPK, TIMP-1In vivo[58]
Promote angiogenesisVEGF, PDGF-BB, PI3K, AktIn vivo[110]
Invigorating Yang to recover circulationSini Decoction Aconite, ginger, and licoriceAntimitochondrial oxidationSOD, MDA, MnSOD mRNAIn vivo[54]

Moving Qi to activate circulationDan-Chuan-Hong Decoction Salvia, Rhizoma Chuanxiong, and safflowerAnti-apoptosisTUNELIn vivo[111]
Enriching Blood to engender fluidDanShen GeGen Decoction Radix Salvia miltiorrhiza, and Radix Puerariae lobataeAntioxidantRedox-sensitive PKCε/mKATP pathwayIn vivo[112]

Enrich Qi and cool Blood Radix et Rhizoma Rhodiolae Kirilowii Radix, Rhizoma Rhodiolae kirilowiiPromote angiogenesisvWF, VEGF, HIF-1α, HIF-1βIn vivo[69]


Mechanism of action in TCM terminologyPatent drug nameMain ingredientMechanismBiomarker/TargetsIn vivo/In vitroReferences

Activating Blood to resolve stasis, and moving Qi to relieve painXinKeShu Tablet Salvia, arrowroot, woody, hawthorn, panaxAntioxidant, promote angiogenesiseNOS; VCAM-1In vivo[113]
TongXinLuo Superfine Ginseng, leeches, scorpion, Eupolyphaga, centipede, et alAntioxidant, proangiogenesisNO, eNOS; vWF, HhcyIn vivo[114]
ShuMai Capsule Peanut shellsPromote angiogenesisvWF, VEGFIn vivo[115]

Moving Qi to activate circulation and relieve painGuanXin ErHao (Guanxin II) Safflower, red peony, salvia, Chuanxiong, and so forthAnti-apoptosis, protect mitochondrial functionCaspase-3, Caspase-9, Bcl-2/Bax, cytochrome c, AktIn vivo[63, 64]
XiongShao Capsule Rhizoma Chuanxiong, Radix Paeoniae RubraAnti-inflammationTNF- , MCP-1, ICIIn vivo[59]

Replenishing Qi to activate circulation, and moving Qi to relieve painVigconic 28 (VI-28) Radix Ginseng, Cornu Cervi, Cordyceps, Radix Salviae, Semen Allii, and so forthAntioxidant, protect mitochondrial functionGSH, -TOC, CuZn-SOD, Ca2+-induced permeability, mitochondrial MDA, Ca2+, cytochrome cIn vivo[116]
Acanthopanax Senticosus Injection AcanthopanaxAntioxidant, inhibit Ca2+ overloadSOD, MDA, GPx; Ca2+In vivo[55]
ShuangShen NingXin Capsule Ginseng total saponins, total salvianolic, corydalisAntioxdiantSOD, MDAIn vivo[117]
ShuangShen TongGuan Recipe Ginseng, astragalus, Atractylodes, and so forthAnti-inflammationNF-κB, p65, TNF- , ICAM-1, MJIC-Cx43In vivo[118]

Replenishing Qi and invigorating Yang ShenFu Injections Red ginseng, MonkshoodAntioxdiant, reduce ME, up-regulate-ATPaseSOD, GPx; LDH, CK; Na+-K+-ATP and Ca2+-ATPIn vivo[119]
Replenishing Blood and activating circulationDanHong Injection Salvia, safflowerAntioxidantSOD, MDAIn vivo [120]
Cardiotonic Pill Salvia miltiorrhizaAnti-apoptosisCaspase-3, AktIn vivo[62]

3.1. Anti-Oxidation

Many Chinese herbal medicines, including extracted compounds, single herbs, decoctions, and patent drugs, exert their beneficial effects on MIR via their anti-oxidative activity. A number of biomarkers have been used to evaluate the antioxidative effects of these Chinese herbal medicines, such as ROS, SOD, GPx, CAT, nitric oxide synthase (NOS), malondialdehyde (MDA), myeloperoxidase (MPO), heme oxygenase (HO)-1, superoxide anion, GOT, 15-F2t-isoprostane (15-F2t-IsoP), ET-1, cycloxygenase-2 (COX-2), thioredoxin-1 (Trx-1), thioredoxin-related protein-32 (TRP32), redox-sensitive PKCε/mKATP pathway, glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GRD), CuZn-superoxide dismutase (CuZn-SOD), and Mn-SOD.

Through in vivo and in vitro experiments, Kim et al. revealed that palmatine, a compound extracted from the Chinese herb, Coptidis rhizome, markedly reduced serum MDA level, and the activity of SOD and CAT in the cardiac tissues, as well as the COX-2 and iNOS expressions in MIR myocardium of rats [49]. Jiang et al. reported that the MDA content and MPO activity in ischemic myocardial tissue of rats treated with Forsythoside B, a compound derived from the Chinese herb, Lamiophlomis rotate (Benth.) Kudo, were both significantly reduced. These reductions were accompanied by a significantly improved recovery in myocardial function [50]. Hwa et al. reported that 2-Methoxycinnamaldehyde (2-MCA), a compound derived from the Chinese herb, Cinnamomum cassia, significantly increased HO-1 induction by promoting the translocation of Nrf-2 from cytosol to nucleus in endothelial cells in an MIR model [51]. In addition, Hu et al. demonstrated that cyclovirobuxine D, a compound derived from the Chinese herb, Buxus microphylla, significantly protected rat aorta endothelial cells against hypoxia-induced injury and enhanced nitric oxide (NO) release from endothelial cells; these effects were inhibited by nitric oxide synthase (NOS) inhibitor N-nitro-L’argininemethyl ester (L-NAME) [52]. Das et al. studied the effects of a single herb, Makhana, and demonstrated that the cardioprotective properties of Makhana were linked to its ability to scavenge ROS [53]. Some decoctions and patent drugs made up of Chinese herbs have also been shown to exert the anti-oxidative effects on MIR. Zhao et al. found that SiNi Decoction (SND), composed of Chinese herbs, Aconite, Ginger and Licorice, could enhance the activity of myocardial and myocyte mitochondrial SOD and reduce MDA by increasing the expression of Mn-SOD mRNA [54]. Wang et al. reported that in rats treated with Acanthopanax Senticosus Injection (ASI) at doses of 25, 50, and 100 mg/kg via femoral vein infusion 30 min after coronary occlusion, the content of myocardial MDA was decreased significantly and dose-dependently and the activities of myocardial SOD and GSH-Px were increased dramatically [55].

3.2. Anti-Inflammation

The manifestation of MIR shares many phenotypic similarities with the activation of a host immune response directed toward invading microorganisms. HSPs and HMGB1 are both involved in the initiation of host defense and tissue repair. Molecules derived from immune cells and cardiomyocytes have been utilized as biomarkers to evaluate the anti-inflammatory effects of Chinese herbal medicine on MIR, including IL-6, MCP-1, TGF-β1, TNF-α, CRP, IL-1β, VCAM-1, ICAM-1, HMGB1, HSP25 and Hsp70, macrophage adhesion molecule-1 (Mac-1), troponinT (Tn-T), phosphorylated p38, activated MAPK, and tissue inhibitor of matrix metalloproteinase (TIMP)-1.

Ren et al. indicated that Tanshinone IIA (Tan IIA), a compound extracted from the Chinese herb, Salvia miltiorrhiza Bunge, attenuated expression of MCP-1, TGF-β1, and TNF-α as well as macrophage infiltration in rats when administered intragastrically at a dose of 60 mg/kg/day [56]. Jiang et al. reported that treatment with Forsythoside B significantly decreased the levels of TNF-β, IL-6, and HMGB1 in a rat MIR model [24, 50]. Results of a study by Chiu and Ko indicated that the reduction of Hsp25 and Hsp70 expression by Schisandrin B (Sch B), a compound extracted from Chinese herb, Schisandra chinensis, in MIR rats resulted in cardioprotection [57]. Shen et al. reported that neutrophils from MIR animals displayed a significant morphological change and Mac-1 up-regulation, both of which could be prevented by Tetrandrine (TTD), a compound extracted from the Chinese herb, Stephania tetrandra [23].

Decoctions and patent drugs made up of Chinese herbs have also been demonstrated to exert anti-inflammatory effects in MIR. Yin et al. showed that a significant reduction in TIMP-1 and TNF levels and improved cardiac function in MIR rats were achieved by treatment with ShuMai Decoction consisting of Astragalus mongholicus Bunge, Salvia miltiorrhiza Bge, and Eupolyphaga sinensis, in a dose-dependent manner [58]. Zhang et al. studied the patent drug Xiongshao Capsule (XSC), comprised of Chinese herbs, Rhizoma Chuanxiong and Radix Paeoniae Rubra, and found that it reduced levels of MCP-1 and TNF-α as well as inflammatory cell infiltration (ICI) in the ischemic myocardium [59].

3.3. Anti-Apoptosis

Alterations of pro and antiapoptotic signaling pathways, including changes in the levels of apoptosis-modulating molecules and induction of caspases, have been used to examine the anti-apoptotic effects of Chinese herbal medicine in MIR. Levels and/or activities of caspase-3, caspase-9, Bcl-2/Bax, p-JNK, p-AMPK, p-p38, phosphatidylinositol 3-kinase (PI3 K), Akt, p-IκB-α, NF-κB, p65, Bcl-2-associated X protein, cytochrome c, and forkhead transcription factor 3 (FOXO3) are among the commonly used biomarkers.

Sun et al. revealed that Salidroside and Tyrosol, two compounds extracted from the Chinese herb, Rhodiola, separately or in combination, significantly reduced caspase-3 activity, cytochrome c release, and JNK activation in an in vitro study [60]. Liu et al. reported that 3,5-Dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester, derived from the Chinese herb, Leonurus, inhibited apoptosis by increasing the ratio of Bcl-2/Bax, decreasing the level of cleaved-caspase-3, and enhancing the phosphorylation of Akt [61]. An in vivo study by Jiang et al. demonstrated that rats treated with Forsythoside B showed a significant recovery in myocardial function due to down-regulated phosphorylation of IkB-α and NF-κB [50].

Ling et al. studied the effects of the patent drug, Cardiotonic Pill (CP) combined with the Chinese herb, Salvia miltiorrhiza, and found that CP treatment (50 mg/mL) significantly inhibited TNF-α-induced apoptosis in cardiomyocytes through activating Akt signaling [62]. Others have showed that Guan xin er hao (Guanxin II), which consists of the Chinese herbs, Safflower, red peony, salvia, Chuanxiong, and Dalbergiae Odoriferae, tilted the balance between Bax and Bcl-2 toward an anti-apoptotic state, decreased mitochondrial cytochrome c release, reduced caspase-9 activation, and attenuated subsequent caspase-3 activation and postischemic myocardial apoptosis in rats [63, 64].

3.4. Protecting Mitochondrial Function

MPTP has been used as a target for protecting mitochondrial function by Chinese herbal medicine in the treatment of MIR. ATP-generation capacity, mitochondrial uncoupling, cAMP response element-binding protein (CREB), cytochrome c, cytochrome P-450, mitochondrial glutathione (GSH), mitochondrial Ca2+, and mitochondrial MDA have been used as biomarkers to evaluate the effects of Chinese herbal medicine.

Wong and Ko reported that a semipurified fraction of Herba Cistanches (HCF1) increased mitochondrial ATP-generation capacity and ADP-stimulated state respiration in H9c2 cardiomyocytes during MIR. HCF1 pretreatment could protect against MIR injury in rats presumably mediated by the induction of glutathione antioxidant [65]. Siu and Ko studied the single Chinese herb, Cistanche, and found it enhanced mitochondrial glutathione status, decreased mitochondrial Ca2+ level, and increased the mitochondrial membrane potential and respiration rate in rat hearts [66]. Others reported that the patent drug, Guanxin II, decreased mitochondrial cytochrome c release and attenuated caspase-3 activation in rat MIR myocardium [63, 64].

3.5. Increasing BMSCs Migration

Bone marrow mesenchymal stem cells (BMSCs) are preferentially attracted to and retained in ischemic tissue. SDF-1 and CXCR4 have been used as targets for increasing BMSC migration to protect cardiomyocytes against MIR.

Tong et al. studied the effect of Tan IIA on MIR both in vitro and in vivo. Their data showed that combination treatment with Tan IIA and BMSCs significantly reduced the infarct size and improved cardiac function after MI, which primarily resulted from Tan IIA induced increase of the migration of BMSCs to ischemic region [67].

3.6. Promoting Angiogenesis

Angiogenesis limits MIR damage by restoring tissue blood flow. Related molecules such as VEGF, von Willebrand factor (vWF), hypoxia-inducible factor 1α (HIF-1α), VEGFR (Flt-1, KDR, and angiopoietin receptor (Tie-2)), platelet-derived growth factor (PDGF-BB), and phosphatidylinositol 3-kinase (PI3K) have been used as the targets for angiogenesis promotion to protect cardiomyocytes against MIR.

Xu et al. found that the compound, Tanshinone IIA, elicited a significant cardioprotective effect by up-regulating VEGF expression in MI rats and enhancing HIF-1α expression [68]. Experiments of Gao et al. showed that the expressions of vWF, HIF-1α, HIF-1β, and VEGF were significantly increased in myocardium treated with Radix et Rhizoma Rhodiolae Kirilowii Decoction [69].

3.7. Up-Regulating KATP Channel Subunits and ATPase, and Inhibiting Calcium Overload

KATP channel subunits Kir6.1, Kir6.2, SUR2A and SUR2B, Na+-K+-ATPase, Ca2+-ATPase and intracellular calcium (Ca2+), and L-type calcium current (I-CaL) have been used to assess the effects of Chinese herbal medicine in protecting cardiomyocytes against MIR.

Han et al. examined the effects of Astragaloside IV (As IV), a compound extracted from the Chinese herb, Astragalus membranaceus. They found that As IV significantly up-regulated mRNA and protein levels of KATP channel subunits Kir6.1, Kir6.2, and SUR2A and SUR2B [70]. Lu and Zhao reported that Lycium barbarum polysaccharides, extracted from the Chinese herb, Lycium barbarum, significantly increased Na+-K+-ATPase and Ca2+-ATPase activities in myocardium of ischemia-reperfusion rats [71].

4. Summary and Perspective

In summary, significant progress has been made regarding the mechanistic research into the efficacy of Chinese herbal medicine for the treatment of MIR. However, much work remains. Most clinical studies were of limited extrapolatable value because of the small sample sizes and/or incomplete data. Experimental studies have focused mainly on single compounds extracted from Chinese herbs. Studies of Chinese decoctions or formulations are relatively scarce, although decoction and formulations are the main forms of therapy in TCM practice. Capitalization of the interactions between the different components and herbs is the essence of TCM. Many herbs are paired together to attenuate toxicity as well as to enhance efficacy. Encouragingly, the number of studies on patent Chinese herbs has been gradually increasing. These studies help us to understand the mechanisms underlying the use of Chinese herbs and formulations for the treatment of MIR. Accordingly, there is a strong likelihood that such ongoing research will lead to novel therapies for the treatment of myocardial ischemia and reperfusion injury using Chinese herbs and herbal formulations.

Abbreviations

ROS: Reactive oxygen species
NOS: Nitric oxide synthase
MDA: Malondialdehyde
SOD: Superoxide dismutase
GSH: Glutathione
GPx: Glutathine peroxidease
MPO: Myeloperoxidase
CAT: Catalase
COX-2: Cycloxygenase-2
GOT: Glutamic oxalacetic transaminase
ME: Myocardial enzymes
TRP32: Thioredoxin-related protein-32
GSH: Glutathione
GSSG: Oxidized glutathione
GRD: Glutathione reductase
CuZn-SOD: CuZn-superoxide dismutase
PI3K: Phosphatidylinositol 3-kinase
HMGB1: High-mobility group box1
HSP: Heat shock protein
TIMP: Tissue inhibitor of matrix metalloproteinase
ICI: Inflammatory cell infiltration
LDH: Lactate dehydrogenase
CK: Creatine kinase
CK-MB: Creatine kinase isoenzyme-MB
TXB2: Thromboxane B2
VEGF: Vascular endothelial growth factor
HIF-1a: Hypoxia-inducible factor 1a
Vwf: Von Willebrand factor
SDF-1: Stromal cell-derived factor-1
SCF-1: Stem cell factor-1
CXCR4: CXC chemokine receptor 4
I-CaL: L-type calcium current
15-F2t-IsoP: 15-F2t-isoprostane
6-keto-PGF1-a: 6-keto-prostaglandin F1alpha
GR: Glucocorticoid receptor
CREB: cAMP response element-binding protein
Tn-T: TroponinT
FOXO3: Forkhead transcription factor 3
Mac-1: Macrophage adhesion molecule-1
HO-1: Heme oxygenase-1
Tie-2: Angiopoietin receptor
TRP32: Thioredoxin-related protein-32
Trx-1: Thioredoxin-1
GSSG: Oxidized glutathione
GRD: Glutathione reductase
PDGF-BB: Platelet-derived growth factor
Hhcy: Hyperhomocysteinemia
MJIC-Cx43: Myocardial junction intercellular communication connexin 43.

Conflict of Interests

The authors declare that they have no conflict of interests regarding the publication of this paper.

Acknowledgment

This work was supported by Grants from the National Institute of Health nos. R21AT006767 and R01HL116626 (to D. Fan).

References

  1. H. K. Eltzschig and T. Eckle, “Ischemia and reperfusion-from mechanism to translation,” Nature Medicine, vol. 17, no. 11, pp. 1391–1401, 2011. View at: Publisher Site | Google Scholar
  2. J. L. Zweier and M. A. H. Talukder, “The role of oxidants and free radicals in reperfusion injury,” Cardiovascular Research, vol. 70, no. 2, pp. 181–190, 2006. View at: Publisher Site | Google Scholar
  3. S.-F. Hsu, K.-C. Niu, C.-L. Lin, and M.-T. Lin, “Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke,” Shock, vol. 26, no. 2, pp. 210–220, 2006. View at: Publisher Site | Google Scholar
  4. I. Barut, O. R. Tarhan, N. Kapucuoglu, R. Sutcu, and Y. Akdeniz, “Lamotrigine reduces intestinal I/R injury in the rat,” Shock, vol. 28, no. 2, pp. 202–206, 2007. View at: Publisher Site | Google Scholar
  5. W.-Y. Lee and S.-M. Lee, “Ischemic preconditioning protects post-ischemic oxidative damage to mitochondria in rat liver,” Shock, vol. 24, no. 4, pp. 370–375, 2005. View at: Publisher Site | Google Scholar
  6. N. Vanlangenakker, T. Vanden Berghe, D. V. Krysko, N. Festjens, and P. Vandenabeele, “Molecular mechanisms and pathophysiology of necrotic cell death,” Current Molecular Medicine, vol. 8, no. 3, pp. 207–220, 2008. View at: Publisher Site | Google Scholar
  7. T. V. Arumugam, P. K. Selvaraj, T. M. Woodruff, and M. P. Mattson, “Targeting ischemic brain injury with intravenous immunoglobulin,” Expert Opinion on Therapeutic Targets, vol. 12, no. 1, pp. 19–29, 2008. View at: Publisher Site | Google Scholar
  8. G. Y. Chen and G. Nuñez, “Sterile inflammation: sensing and reacting to damage,” Nature Reviews Immunology, vol. 10, no. 12, pp. 826–837, 2010. View at: Publisher Site | Google Scholar
  9. L. Yu, L. Wang, and S. Chen, “Endogenous toll-like receptor ligands and their biological significance,” Journal of Cellular and Molecular Medicine, vol. 14, no. 11, pp. 2592–2603, 2010. View at: Publisher Site | Google Scholar
  10. D. Fan, A. Takawale, J. Lee, and Z. Kassiri, “Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease,” Fibrogenesis & Tissue Repair, vol. 5, no. 1, p. 15, 2012. View at: Google Scholar
  11. Y. Wang, A. M. Abarbanell, J. L. Herrmann et al., “Toll-like receptor signaling pathways and the evidence linking toll-like receptor signaling to cardiac ischemia/reperfusion injury,” Shock, vol. 34, no. 6, pp. 548–557, 2010. View at: Publisher Site | Google Scholar
  12. D. J. Kaczorowski, A. Nakao, K. R. McCurry, and T. R. Billiar, “Toll-like receptors and myocardial ischemia/reperfusion, inflammation, and injury,” Current Cardiology Reviews, vol. 5, no. 3, pp. 196–202, 2009. View at: Publisher Site | Google Scholar
  13. J.-I. Oyama, C. Blais Jr., X. Liu et al., “Reduced myocardial ischemia-reperfusion Injury in toll-like receptor 4-deficient mice,” Circulation, vol. 109, no. 6, pp. 784–789, 2004. View at: Publisher Site | Google Scholar
  14. T. Shishido, N. Nozaki, S. Yamaguchi et al., “Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction,” Circulation, vol. 108, no. 23, pp. 2905–2910, 2003. View at: Publisher Site | Google Scholar
  15. J. G. Vallejo, “Role of Toll-like receptors in cardiovascular diseases,” Clinical Science, vol. 121, no. 1, pp. 1–10, 2011. View at: Publisher Site | Google Scholar
  16. J. H. Boyd, S. Mathur, Y. Wang, R. M. Bateman, and K. R. Walley, “Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-κB dependent inflammatory response,” Cardiovascular Research, vol. 72, no. 3, pp. 384–393, 2006. View at: Publisher Site | Google Scholar
  17. S. K. Calderwood, S. S. Mambula, and P. J. Gray Jr., “Extracellular heat shock proteins in cell signaling and immunity,” Annals of the New York Academy of Sciences, vol. 1113, pp. 28–39, 2007. View at: Publisher Site | Google Scholar
  18. S.-C. Kim, J. P. Stice, L. Chen et al., “Extracellular heat shock protein 60, cardiac myocytes, and apoptosis,” Circulation Research, vol. 105, no. 12, pp. 1186–1195, 2009. View at: Publisher Site | Google Scholar
  19. I. E. Dumitriu, P. Baruah, A. A. Manfredi, M. E. Bianchi, and P. Rovere-Querini, “HMGB1: guiding immunity from within,” Trends in Immunology, vol. 26, no. 7, pp. 381–387, 2005. View at: Publisher Site | Google Scholar
  20. M. Andrassy, H. C. Volz, J. C. Igwe et al., “High-mobility group box-1 in ischemia-reperfusion injury of the heart,” Circulation, vol. 117, no. 25, pp. 3216–3226, 2008. View at: Publisher Site | Google Scholar
  21. P. F. Hwang, N. Porterfield, D. Pannell, T. A. Davis, and E. A. Elster, “Trauma is danger,” Journal of Translational Medicine, vol. 9, no. 1, article 92, 2011. View at: Publisher Site | Google Scholar
  22. S. L. Deshmane, S. Kremlev, S. Amini, and B. E. Sawaya, “Monocyte chemoattractant protein-1 (MCP-1): an overview,” Journal of Interferon and Cytokine Research, vol. 29, no. 6, pp. 313–325, 2009. View at: Publisher Site | Google Scholar
  23. Y.-C. Shen, C.-F. Chen, and Y.-J. Sung, “Tetrandrine ameliorates ischaemia-reperfusion injury of rat myocardium through inhibition of neutrophil priming and activation,” British Journal of Pharmacology, vol. 128, no. 7, pp. 1593–1601, 1999. View at: Google Scholar
  24. J. B. Kubavat and S. M. B. Asdaq, “Role of Sida cordifolia L. leaves on biochemical and antioxidant profile during myocardial injury,” Journal of Ethnopharmacology, vol. 124, no. 1, pp. 162–165, 2009. View at: Publisher Site | Google Scholar
  25. I. R. Mohanty, U. Maheshwari, D. Joseph, and Y. Deshmukh, “Bacopa monniera protects rat heart against ischaemia-reperfusion injury: role of key apoptotic regulatory proteins and enzymes,” Journal of Pharmacy and Pharmacology, vol. 62, no. 9, pp. 1175–1184, 2010. View at: Publisher Site | Google Scholar
  26. P. P. Babu, G. Suzuki, Y. Ono, and Y. Yoshida, “Attenuation of ischemia and/or reperfusion injury during myocardial infarction using mild hypothermia in rats: an immunohistochemical study of Bcl-2, Bax, Bak and TUNEL,” Pathology International, vol. 54, no. 12, pp. 896–903, 2004. View at: Publisher Site | Google Scholar
  27. Y. Matsui, H. Takagi, X. Qu et al., “Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and beclin 1 in mediating autophagy,” Circulation Research, vol. 100, no. 6, pp. 914–922, 2007. View at: Publisher Site | Google Scholar
  28. E. J. Miller, J. Li, L. Leng et al., “Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart,” Nature, vol. 451, no. 7178, pp. 578–582, 2008. View at: Publisher Site | Google Scholar
  29. D. Qi, X. Hu, X. Wu et al., “Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion,” Journal of Clinical Investigation, vol. 119, no. 12, pp. 3807–3816, 2009. View at: Publisher Site | Google Scholar
  30. H. Kanda and M. Miura, “Regulatory roles of JNK in programmed cell death,” Journal of Biochemistry, vol. 136, no. 1, pp. 1–6, 2004. View at: Publisher Site | Google Scholar
  31. H.-M. Shen and Z.-G. Liu, “JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species,” Free Radical Biology and Medicine, vol. 40, no. 6, pp. 928–939, 2006. View at: Publisher Site | Google Scholar
  32. N. Hanawa, M. Shinohara, B. Saberi, W. A. Gaarde, D. Han, and N. Kaplowitz, “Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury,” Journal of Biological Chemistry, vol. 283, no. 20, pp. 13565–13577, 2008. View at: Publisher Site | Google Scholar
  33. Y. Zhao and T. Herdegen, “Cerebral ischemia provokes a profound exchange of activated JNK isoforms in brain mitochondria,” Molecular and Cellular Neuroscience, vol. 41, no. 2, pp. 186–195, 2009. View at: Publisher Site | Google Scholar
  34. Q. Zhou, P. Y. Lam, D. Han, and E. Cadenas, “c-Jun N-terminal kinase regulates mitochondrial bioenergetics by modulating pyruvate dehydrogenase activity in primary cortical neurons,” Journal of Neurochemistry, vol. 104, no. 2, pp. 325–335, 2008. View at: Publisher Site | Google Scholar
  35. Q. Zhou, P. Y. Lam, D. Han, and E. Cadenas, “Activation of c-Jun-N-terminal kinase and decline of mitochondrial pyruvate dehydrogenase activity during brain aging,” FEBS Letters, vol. 583, no. 7, pp. 1132–1140, 2009. View at: Publisher Site | Google Scholar
  36. E. P. Cummins, E. Berra, K. M. Comerford et al., “Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 48, pp. 18154–18159, 2006. View at: Publisher Site | Google Scholar
  37. T. Ha, L. Liu, J. Kelley, R. Kao, D. Williams, and C. Li, “Toll-like receptors: new players in myocardial ischemia/reperfusion injury,” Antioxidants and Redox Signaling, vol. 15, no. 7, pp. 1875–1893, 2011. View at: Publisher Site | Google Scholar
  38. M. T. Crow, K. Mani, Y.-J. Nam, and R. N. Kitsis, “The mitochondrial death pathway and cardiac myocyte apoptosis,” Circulation Research, vol. 95, no. 10, pp. 957–970, 2004. View at: Publisher Site | Google Scholar
  39. E. Murphy and C. Steenbergen, “Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury,” Physiological Reviews, vol. 88, no. 2, pp. 581–609, 2008. View at: Publisher Site | Google Scholar
  40. H. J. Jin, X. L. Xie, J. M. Ye, and C. G. Li, “TanshinoneIIA and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells,” PloS One, vol. 8, no. 1, article e51720, 2013. View at: Google Scholar
  41. G. Chamberlain, J. Fox, B. Ashton, and J. Middleton, “Concise review: Mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing,” Stem Cells, vol. 25, no. 11, pp. 2739–2749, 2007. View at: Publisher Site | Google Scholar
  42. N. Nagaya, T. Fujii, T. Iwase et al., “Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 287, no. 6, pp. H2670–H2676, 2004. View at: Publisher Site | Google Scholar
  43. J. Hoffmann, A. J. Glassford, T. C. Doyle, R. C. Robbins, S. Schrepfer, and M. P. Pelletier, “Angiogenic effects despite limited cell survival of bone marrow-derived mesenchymal stem cells under ischemia,” Thoracic and Cardiovascular Surgeon, vol. 58, no. 3, pp. 136–142, 2010. View at: Publisher Site | Google Scholar
  44. S. Kuroda, “Bone marrow stromal cell transplantation for ischemic stroke—its multi-functional feature,” Acta Neurobiologiae Experimentalis, vol. 73, no. 1, pp. 57–65, 2013. View at: Google Scholar
  45. R. Tabibiazar and S. G. Rockson, “Angiogenesis and the ischaemic heart,” European Heart Journal, vol. 22, no. 11, pp. 903–918, 2001. View at: Publisher Site | Google Scholar
  46. S. Fukuda, S. Kaga, H. Sasaki et al., “Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction,” Journal of Molecular and Cellular Cardiology, vol. 36, no. 4, pp. 547–559, 2004. View at: Publisher Site | Google Scholar
  47. S. Ylä-Herttuala, T. T. Rissanen, I. Vajanto, and J. Hartikainen, “Vascular endothelial growth factors. Biology and current status of clinical applications in cardiovascular medicine,” Journal of the American College of Cardiology, vol. 49, no. 10, pp. 1015–1026, 2007. View at: Publisher Site | Google Scholar
  48. I. Friehs, R. Barillas, N. V. Vasilyev, N. Roy, F. X. McGowan, and P. J. Del Nido, “Vascular endothelial growth factor prevents apoptosis and preserves contractile function in hypertrophied infant heart,” Circulation, vol. 114, no. 1, pp. I290–I295, 2006. View at: Publisher Site | Google Scholar
  49. Y. M. Kim, Y. M. Ha, Y. C. Jin et al., “Palmatine from Coptidis rhizoma reduces ischemia-reperfusion-mediated acute myocardial injury in the rat,” Food and Chemical Toxicology, vol. 47, no. 8, pp. 2097–2102, 2009. View at: Publisher Site | Google Scholar
  50. W.-L. Jiang, F.-H. Fu, B.-M. Xu, J.-W. Tian, H.-B. Zhu, and J.-H. Jian-Hou, “Cardioprotection with forsythoside B in rat myocardial ischemia-reperfusion injury: relation to inflammation response,” Phytomedicine, vol. 17, no. 8-9, pp. 635–639, 2010. View at: Publisher Site | Google Scholar
  51. J. S. Hwa, Y. C. Jin, Y. S. Lee et al., “2-Methoxycinnamaldehyde from Cinnamomum cassia reduces rat myocardial ischemia and reperfusion injury in vivo due to HO-1 induction,” Journal of Ethnopharmacology, vol. 139, no. 2, pp. 605–615, 2012. View at: Publisher Site | Google Scholar
  52. D. Hu, X. Liu, Y. Wang, and S. Chen, “Cyclovirobuxine D ameliorates acute myocardial ischemia by KATP channel opening, nitric oxide release and anti-thrombosis,” European Journal of Pharmacology, vol. 569, no. 1-2, pp. 103–109, 2007. View at: Publisher Site | Google Scholar
  53. S. Das, P. Der, U. Raychaudhuri, N. Maulik, and D. K. Das, “The effect of Euryale ferox (makhana), an herb of aquatic origin, on myocardial ischemic reperfusion injury,” Molecular and Cellular Biochemistry, vol. 289, no. 1-2, pp. 55–63, 2006. View at: Publisher Site | Google Scholar
  54. D.-Y. Zhao, M.-Q. Zhao, and W.-K. Wu, “Study on activity and mechanism of Sini Decoction anti-mitochondrial oxidation injury caused by myocardial ischemia/reperfusion,” Zhong Yao Cai, vol. 31, no. 11, pp. 1681–1685, 2008. View at: Google Scholar
  55. L. Wang, X.-F. Yu, S.-C. Qu, H.-L. Xu, and D.-Y. Sui, “Effects of CASI on myocardial ischemia-reperfusion arrhythmia in rats,” Zhongguo Zhongyao Zazhi, vol. 32, no. 20, pp. 2174–2177, 2007. View at: Google Scholar
  56. Z. H. Ren, Y. H. Tong, W. Xu, J. Ma, and Y. Chen, “Tanshinone II A attenuates inflammatory responses of rats with myocardial infarction by reducing MCP-1 expression,” Phytomedicine, vol. 17, no. 3-4, pp. 212–218, 2010. View at: Publisher Site | Google Scholar
  57. P. Y. Chiu and K. M. Ko, “Schisandrin B protects myocardial ischemia-reperfusion injury partly by inducing Hsp25 and Hsp70 expression in rats,” Molecular and Cellular Biochemistry, vol. 266, no. 1-2, pp. 139–144, 2004. View at: Publisher Site | Google Scholar
  58. H.-Q. Yin, B. Wang, J.-D. Zhang et al., “Effect of traditional Chinese medicine Shu-Mai-Tang on attenuating TNFα-induced myocardial fibrosis in myocardial ischemia rats,” Journal of Ethnopharmacology, vol. 118, no. 1, pp. 133–139, 2008. View at: Publisher Site | Google Scholar
  59. N. Zhang, E. R. Chen, and Y. Y. Zhang, “Effect of Guanxinkang on ATP-sensitive potassium channel in myocardial cells of rat with ischemic/ reperfusion injury,” Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi, vol. 30, no. 11, pp. 1186–1189, 2010. View at: Google Scholar
  60. L. Sun, C. K. Isaak, Y. Zhou, J. C. Petkau, K. O. Y. Liu, and Y. L. Siow, “Salidroside and tyrosol from Rhodiola protect H9c2 cells from ischemia/reperfusion-induced apoptosis,” Life Sciences, vol. 91, no. 5-6, pp. 151–158, 2012. View at: Google Scholar
  61. C. Liu, W. Guo, S. Maerz, X. Gu, and Y. Zhu, “3, 5-Dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester: a novel twin drug that prevents primary cardiac myocytes from hypoxia-induced apoptosis,” European Journal of Pharmacology, vol. 700, no. 1–3, pp. 118–126, 2013. View at: Google Scholar
  62. S. Ling, R. Luo, A. Dai, Z. Guo, R. Guo, and P. A. Komesaroff, “A pharmaceutical preparation of Salvia miltiorrhiza protects cardiac myocytes from tumor necrosis factor-induced apoptosis and reduces angiotensin II-stimulated collagen synthesis in fibroblasts,” Phytomedicine, vol. 16, no. 1, pp. 56–64, 2009. View at: Publisher Site | Google Scholar
  63. J. Zhao, X. Huang, W. Tang et al., “Effect of oriental herbal prescription Guan-Xin-Er-Hao on coronary flow in healthy volunteers and antiapoptosis on myocardial ischemia-reperfusion in rat models,” Phytotherapy Research, vol. 21, no. 10, pp. 926–931, 2007. View at: Publisher Site | Google Scholar
  64. H.-W. Zhao, F. Qin, Y.-X. Liu, X. Huang, and P. Ren, “Antiapoptotic mechanisms of Chinese medicine formula, Guan-Xin-Er-Hao, in the rat ischemic heart,” Tohoku Journal of Experimental Medicine, vol. 216, no. 4, pp. 309–316, 2008. View at: Publisher Site | Google Scholar
  65. H. S. Wong and K. M. Ko, “Herba Cistanches stimulates cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration in H9c2 cardiomyocytes,” Pharmaceutical Biology, vol. 51, no. 1, pp. 64–73, 2013. View at: Google Scholar
  66. A. H.-L. Siu and K. M. Ko, “Herba Cistanche extract enhances mitochondrial glutathione status and respiration in rat hearts, with possible induction of uncoupling proteins,” Pharmaceutical Biology, vol. 48, no. 5, pp. 512–517, 2010. View at: Publisher Site | Google Scholar
  67. Y. Tong, W. Xu, H. Han et al., “Tanshinone IIA increases recruitment of bone marrow mesenchymal stem cells to infarct region via up-regulating stromal cell-derived factor-1/CXC chemokine receptor 4 axis in a myocardial ischemia model,” Phytomedicine, vol. 18, no. 6, pp. 443–450, 2011. View at: Publisher Site | Google Scholar
  68. W. Xu, J. Yang, and L.-M. Wu, “Cardioprotective effects of tanshinone IIA on myocardial ischemia injury in rats,” Pharmazie, vol. 64, no. 5, pp. 332–336, 2009. View at: Publisher Site | Google Scholar
  69. X.-F. Gao, H.-M. Shi, T. Sun, and H. Ao, “Effects of Radix et Rhizoma Rhodiolae Kirilowii on expressions of von Willebrand factor, hypoxia-inducible factor 1 and vascular endothelial growth factor in myocardium of rats with acute myocardial infarction,” Journal of Chinese Integrative Medicine, vol. 7, no. 5, pp. 434–440, 2009. View at: Publisher Site | Google Scholar
  70. X.-H. Han, P. Liu, Y.-Y. Zhang, N. Zhang, F.-R. Chen, and J.-F. Cai, “Astragaloside IV regulates expression of ATP-sensitive potassium channel subunits after ischemia-reperfusion in rat ventricular cardiomyocytes,” Journal of Traditional Chinese Medicine, vol. 31, no. 4, pp. 321–326, 2011. View at: Google Scholar
  71. S. P. Lu and P. T. Zhao, “Chemical characterization of Lycium barbarum polysaccharides and their reducing myocardial injury in ischemia/reperfusion of rat heart,” International Journal of Biological Macromolecules, vol. 47, no. 5, pp. 681–684, 2010. View at: Publisher Site | Google Scholar
  72. J. Fu, H. Huang, J. Liu, R. Pi, J. Chen, and P. Liu, “Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis,” European Journal of Pharmacology, vol. 568, no. 1–3, pp. 213–221, 2007. View at: Publisher Site | Google Scholar
  73. R. Yang, A. Liu, X. Ma, L. Li, D. Su, and J. Liu, “Sodium tanshinone IIA sulfonate protects cardiomyocytes against oxidative stress-mediated apoptosis through inhibiting JNK activation,” Journal of Cardiovascular Pharmacology, vol. 51, no. 4, pp. 396–401, 2008. View at: Publisher Site | Google Scholar
  74. K. K. W. Au-Yeung, O. Karmin, P. C. Choy, D.-Y. Zhu, and Y. L. Siow, “Magnesium tanshinoate B protects endothelial cells against oxidized lipoprotein-induced apoptosis,” Canadian Journal of Physiology and Pharmacology, vol. 85, no. 11, pp. 1053–1062, 2007. View at: Publisher Site | Google Scholar
  75. B. Wang, J.-X. Liu, H.-X. Meng, and C.-R. Lin, “Blocking effect of salvianolic acid a on calcium channels in isolated rat ventricular myocytes,” Chinese Journal of Integrative Medicine, vol. 18, no. 5, pp. 366–370, 2012. View at: Publisher Site | Google Scholar
  76. H.-B. He, X.-Z. Yang, M.-Q. Shi, X.-W. Zeng, L.-M. Wu, and L.-D. Li, “Comparison of cardioprotective effects of salvianolic acid B and benazepril on large myocardial infarction in rats,” Pharmacological Reports, vol. 60, no. 3, pp. 369–381, 2008. View at: Google Scholar
  77. R. Nie, R. Xia, X. Zhong, and Z. Xia, “Salvia miltiorrhiza treatment during early reperfusion reduced postischemic myocardial injury in the rat,” Canadian Journal of Physiology and Pharmacology, vol. 85, no. 10, pp. 1012–1019, 2007. View at: Publisher Site | Google Scholar
  78. Q.-X. Yue, F.-B. Xie, X.-Y. Song et al., “Proteomic studies on protective effects of salvianolic acids, notoginsengnosides and combination of salvianolic acids and notoginsengnosides against cardiac ischemic-reperfusion injury,” Journal of Ethnopharmacology, vol. 141, no. 2, pp. 659–667, 2012. View at: Publisher Site | Google Scholar
  79. X. Wang, Y. Wang, M. Jiang et al., “Differential cardioprotective effects of salvianolic acid and tanshinone on acute myocardial infarction are mediated by unique signaling pathways,” Journal of Ethnopharmacology, vol. 135, no. 3, pp. 662–671, 2011. View at: Publisher Site | Google Scholar
  80. C. Pan, L. Lou, Y. Huo et al., “Salvianolic acid B and Tanshinone IIA attenuate myocardial ischemia injury in mice by no production through multiple pathways,” Therapeutic Advances in Cardiovascular Disease, vol. 5, no. 2, pp. 99–111, 2011. View at: Publisher Site | Google Scholar
  81. L. Wu, H. Qiao, Y. Li, and L. Li, “Protective roles of puerarin and Danshensu on acute ischemic myocardial injury in rats,” Phytomedicine, vol. 14, no. 10, pp. 652–658, 2007. View at: Publisher Site | Google Scholar
  82. R. Zhou, L.-F. He, Y.-J. Li, Y. Shen, R.-B. Chao, and J.-R. Du, “Cardioprotective effect of water and ethanol extract of Salvia miltiorrhiza in an experimental model of myocardial infarction,” Journal of Ethnopharmacology, vol. 139, no. 2, pp. 440–446, 2012. View at: Publisher Site | Google Scholar
  83. J. Sun, S. H. Huang, B. K.-H. Tan et al., “Effects of purified herbal extract of Salvia miltiorrhiza on ischemic rat myocardium after acute myocardial infarction,” Life Sciences, vol. 76, no. 24, pp. 2849–2860, 2005. View at: Publisher Site | Google Scholar
  84. D.-W. Zhang, J.-G. Liu, J.-T. Feng et al., “Effects of effective components compatibility of aqueous extracts of Salviae Miltiorrhizae and Rhizoma Chuanxiong on rat myocardial ischemia/reperfusion injury,” Chinese Critical Care Medicine, vol. 22, no. 2, pp. 109–112, 2010. View at: Publisher Site | Google Scholar
  85. H.-C. Wang, H. Zhang, and T.-L. Zhou, “Protective effect of hydrophilic Salvia monomer on liver ischemia/reperfusion injury induced by pro-inflammatory cytokines,” Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi, vol. 22, no. 3, pp. 207–210, 2002. View at: Google Scholar
  86. X. Q. Yi, T. Li, J. R. Wang et al., “Total ginsenosides increase coronary perfusion flow in isolated rat hearts through activation of PI3K/Akt-eNOS signaling,” Phytomedicine, vol. 17, no. 13, pp. 1006–1015, 2010. View at: Publisher Site | Google Scholar
  87. J. R. Wang, H. Zhou, X. Q. Yi, Z. H. Jiang, and L. Liu, “Total ginsenosides of Radix Ginseng modulates tricarboxylic acid cycle protein expression to enhance cardiac energy metabolism in ischemic rat heart tissues,” Molecules, vol. 17, no. 11, pp. 12746–12757, 2012. View at: Google Scholar
  88. J.-H. Feng, Q. Shi, Y. Wang, and Y.-Y. Cheng, “Effects of Radix Ginseng and Radix Ophiopogonis extract (SMF) on protein S-nitrosylation in ischemic myocardial tissue,” Zhongguo Zhongyao Zazhi, vol. 33, no. 15, pp. 1894–1897, 2008. View at: Google Scholar
  89. J. Jian, F. Qing, S. Zhang, J. Huang, and R. Huang, “The effect of 17-methoxyl-7-hydroxy-benzene-furanchalcone isolated from Millettia pulchra on myocardial ischemia in vitro and in vivo,” Planta Medica, vol. 78, no. 12, pp. 1324–1331, 2012. View at: Google Scholar
  90. N. Chen and K. M. Ko, “Schisandrin B-induced glutathione antioxidant response and cardioprotection are mediated by reactive oxidant species production in rat hearts,” Biological and Pharmaceutical Bulletin, vol. 33, no. 5, pp. 825–829, 2010. View at: Publisher Site | Google Scholar
  91. S.-Y. Chen, G. Hsiao, H.-R. Hwang, P.-Y. Cheng, and Y.-M. Lee, “Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats,” Journal of Biomedical Science, vol. 13, no. 5, pp. 731–740, 2006. View at: Publisher Site | Google Scholar
  92. S. Y. Han, H. X. Li, X. Ma et al., “Evaluation of the anti-myocardial ischemia effect of individual and combined extracts of Panax notoginseng and Carthamus tinctorius in rats,” Journal of Ethnopharmacology, vol. 145, no. 3, pp. 722–727, 2013. View at: Google Scholar
  93. S.-Y. Han, H.-X. Li, X. Ma, K. Zhang, Z.-Z. Ma, and P.-F. Tu, “Protective effects of purified safflower extract on myocardial ischemia in vivo and in vitro,” Phytomedicine, vol. 16, no. 8, pp. 694–702, 2009. View at: Publisher Site | Google Scholar
  94. C. Li, Z. Liu, J. Tian et al., “Protective roles of Asperosaponin VI, a triterpene saponin isolated from Dipsacus asper Wall on acute myocardial infarction in rats,” European Journal of Pharmacology, vol. 627, no. 1–3, pp. 235–241, 2010. View at: Publisher Site | Google Scholar
  95. C. Li, J. Tian, G. Li et al., “Asperosaponin VI protects cardiac myocytes from hypoxia-induced apoptosis via activation of the PI3K/Akt and CREB pathways,” European Journal of Pharmacology, vol. 649, no. 1–3, pp. 100–107, 2010. View at: Publisher Site | Google Scholar
  96. C.-J. Ding, J.-T. Liu, J.-X. Wang et al., “Protective effect of total flavonoid of Herba Pyrolae on acute myocardial ischemic injury in rats,” Zhong Yao Cai, vol. 30, no. 9, pp. 1105–1109, 2007. View at: Google Scholar
  97. G. A. Kurian and J. Paddikkala, “Methanol extract of Desmodium gangeticum DC root mimetic post-conditioning effect in isolated perfused rat heart by stimulating muscarinic receptors,” Asian Pacific Journal of Tropical Medicine, vol. 5, no. 6, pp. 448–454, 2012. View at: Publisher Site | Google Scholar
  98. X.-H. Liu, P.-F. Chen, L.-L. Pan, R. D. Silva, and Y.-Z. Zhu, “4-Guanidino-n-butyl syringate (Leonurine, SCM 198) protects H9c2 rat ventricular cells from hypoxia-induced apoptosis,” Journal of Cardiovascular Pharmacology, vol. 54, no. 5, pp. 437–444, 2009. View at: Publisher Site | Google Scholar
  99. M. Kang, J.-H. Kim, C. Cho et al., “Effect of Acori graminei Rhizoma on contractile dysfunction of ischemic and reperfused rat heart,” Biological and Pharmaceutical Bulletin, vol. 29, no. 3, pp. 483–488, 2006. View at: Publisher Site | Google Scholar
  100. J. Wang, H. Ma, X. Zhang et al., “A novel AMPK activator from Chinese herb medicine and ischemia phosphorylate the cardiac transcription factor FOXO3,” International Journal of Physiology, Pathophysiology and Pharmacology, vol. 1, no. 2, pp. 116–126, 2009. View at: Google Scholar
  101. E. Chan, X.-X. Liu, D.-J. Guo et al., “Extract of scutellaria baicalensis georgi root exerts protection against myocardial ischemia-reperfusion injury in rats,” American Journal of Chinese Medicine, vol. 39, no. 4, pp. 693–704, 2011. View at: Publisher Site | Google Scholar
  102. C.-Z. Wang, S. R. Mehendale, T. Calway, and C.-S. Yuan, “Botanical flavonoids on coronary heart disease,” American Journal of Chinese Medicine, vol. 39, no. 4, pp. 661–671, 2011. View at: Publisher Site | Google Scholar
  103. J.-Y. Zhou, H.-F. Liao, and G.-Y. Huang, “A pharmacology study of Cyclovirobuxinum D on curing myocardial ischemia induced by isoprenaline,” Zhong Yao Cai, vol. 29, no. 11, pp. 1218–1220, 2006. View at: Google Scholar
  104. H. Ling, L. Wu, and L. Li, “Corydalis yanhusuo rhizoma extract reduces infarct size and improves heart function during myocardial ischemia/reperfusion by inhibiting apoptosis in rats,” Phytotherapy Research, vol. 20, no. 6, pp. 448–453, 2006. View at: Publisher Site | Google Scholar
  105. Y.-M. Lee, G. Hsiao, H.-R. Chen, Y.-C. Chen, J.-R. Sheu, and M.-H. Yen, “Magnolol reduces myocardial ischemia/reperfusion injury via neutrophil inhibition in rats,” European Journal of Pharmacology, vol. 422, no. 1–3, pp. 159–167, 2001. View at: Publisher Site | Google Scholar
  106. J. Li, W.-H. Fan, and H. Ao, “Effect of rhodiola on expressions of Flt-1, KDR and Tie-2 in rats with ischemic myocardium,” Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi, vol. 25, no. 5, pp. 445–448, 2005. View at: Google Scholar
  107. M. Kang, J.-H. Kim, C. Cho et al., “Anti-ischemic effect of Aurantii Fructus on contractile dysfunction of ischemic and reperfused rat heart,” Journal of Ethnopharmacology, vol. 111, no. 3, pp. 584–591, 2007. View at: Publisher Site | Google Scholar
  108. D. H. F. Mak, P. Y. Chiu, T. T. X. Dong, K. W. K. Tsim, and K. M. Ko, “Dang-Gui Buxue Tang produces a more potent cardioprotective effect than its component herb extracts and enhances glutathione status in rat heart mitochondria and erythrocytes,” Phytotherapy Research, vol. 20, no. 7, pp. 561–567, 2006. View at: Publisher Site | Google Scholar
  109. Y. Liu, R. Lin, H. Zhang, J.-Y. Zhang, Q.-L. Ji, and Y.-J. Yang, “Protective effect of Buyanghuanwu Decoction on myocardial ischemia induced by isoproterenol in rats,” Zhong Yao Cai, vol. 32, no. 3, pp. 380–383, 2009. View at: Google Scholar
  110. H. Yin, J. Zhang, H. Lin et al., “Effect of traditional chinese medicine shu-mai-tang on angiogenesis, arteriogenesis and cardiac function in rats with myocardial ischemia,” Phytotherapy Research, vol. 23, no. 1, pp. 92–98, 2009. View at: Publisher Site | Google Scholar
  111. X.-Y. Wang, F. Qin, X. Huang, X.-Y. Zhang, P. Ren, and H.-W. Zhao, “Effects of Dan-Chuan-Hong decoction on myocardial apoptosis of acute myocardial ischemia in rats,” Zhong Yao Cai, vol. 32, no. 5, pp. 725–728, 2009. View at: Google Scholar
  112. P. Y. Chiu, S. M. Wong, H. Y. Leung et al., “Acute treatment with Danshen-Gegen decoction protects the myocardium against ischemia/reperfusion injury via the redox-sensitive PKCε/mKATP pathway in rats,” Phytomedicine, vol. 18, no. 11, pp. 916–925, 2011. View at: Publisher Site | Google Scholar
  113. T. Xu, J.-B. Peng, W.-T. Zhang et al., “Antiatherogenic and anti-ischemic properties of traditional Chinese medicine xinkeshu via endothelial protecting function,” Evidence-based Complementary and Alternative Medicine, vol. 2012, Article ID 302137, 9 pages, 2012. View at: Publisher Site | Google Scholar
  114. Y.-L. Han, C. Cheng, H.-M. Tan et al., “Effect of Tongxinluo superfine on experimental anginal model (contraction of collaterals) in rat with endothelial dysfunction,” Zhongguo Zhongyao Zazhi, vol. 32, no. 22, pp. 2404–2426, 2007. View at: Google Scholar
  115. H.-Q. Yin, J.-D. Zhang, and H.-Q. Lin, “Experimental study on effect of Shumai capsule in promoting angiogenesis in rats with myocardial ischemia,” Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi, vol. 27, no. 11, pp. 1020–1022, 2007. View at: Google Scholar
  116. P. Y. Chiu, H. Y. Leung, A. H. Ling Siu, N. Chen, M. K. T. Poon, and K. M. Ko, “Long-term treatment with a Yang-invigorating Chinese herbal formula produces generalized tissue protection against oxidative damage in rats,” Rejuvenation Research, vol. 11, no. 1, pp. 43–62, 2008. View at: Publisher Site | Google Scholar
  117. Z. Yu, J.-X. Liu, X.-Z. Li, X.-H. Shang, A.-G. Yan, and X.-Q. Feng, “Protective effects of Shuangshen Ningxin capsule on miniature swine after myocardial ischemia by intervention,” Zhongguo Zhongyao Zazhi, vol. 32, no. 16, pp. 1695–1699, 2007. View at: Google Scholar
  118. J.-X. Liu, X. Han, and X.-B. Ma, “Effect of Shuangshen Tongguan Recipe on nuclear factor-kappa B signal pathway and myocardial junction-mediated intercellular communication in acute myocardial ischemia/reperfusion injured model rats,” Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi, vol. 25, no. 3, pp. 228–231, 2005. View at: Google Scholar
  119. Z. F. Wang, “The protective of Shenfu injections on hemodynamics and myocardial enzyme after myocardial ischemia/reperfusion injury,” Zhongguo Ying Yong Sheng Li Xue Za Zhi, vol. 27, no. 2, pp. 155–157, 2011. View at: Google Scholar
  120. X.-J. Ma, S.-J. Yin, J.-C. Jin et al., “Synergistic protection of danhong injection and ischemic postconditioning on myocardial reperfusion injury in minipigs,” Chinese Journal of Integrative Medicine, vol. 16, no. 6, pp. 531–536, 2010. View at: Publisher Site | Google Scholar

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