Background. Doxorubicin (DOX) is one of the most potent and widely prescribed antitumor agents; however, its clinical use is limited by cardiac side effects. In this study, we aimed to clarify the protective effects of Qiliqiangxin (QL), a traditional Chinese medicine formulation, on DOX-induced cardiotoxicity and to explore the underlying mechanisms in a rat model. Methods. Male Sprague-Dawley rats were randomly assigned to three groups with different interventions (control, DOX, and DOX plus QL) for 31 days. Cardiac function was monitored. The levels of oxidative stress in plasm were detected, the activities of autophagy and apoptosis in rat hearts were determined, and then, the related PI3K/AKT/mTOR signal pathway regulating apoptosis and autophagy was investigated. Results. QL improved cardiac dysfunction and decreased the increased level of cardiac enzymes in plasm caused by DOX. Moreover, DOX exposure resulted in oxidative stress enhancement, which was suppressed by QL treatment. Then, we discovered that DOX intervention caused the apoptosis of cardiomyocytes by activating the mitochondrial-dependent apoptotic pathway which was strongly inhibited by QL treatment. Furthermore, there was a significant increase in autophagic activities in the DOX-stimulated myocardium. Administration of QL substantially inhibited the enhanced autophagic activities, which might be attributed to the activation of PI3K/AKT/mTOR cascade, followed by suppression of ULK1 activity. Conclusions. QL exhibited protective roles against DOX-induced cardiotoxicity possibly via mediating the PI3K/AKT/mTOR pathway, leading to inhibition of autophagy and subsequent apoptosis activities.

Yating Qin

Chao Lv

Xinxin Zhang

Weibin Ruan

Xiangyu Xu

Chen Chen

Xiaoning Wan

Xinyun Ji

Juan Zhou

Li Lu

Xiaomei Guo

Protective Effect of Qiliqiangxin against Doxorubicin-Induced Cardiomyopathy by Suppressing Excessive Autophagy and Apoptosis

Background. Some studies suggest that potential safety issues about PCSK9 inhibitors have not been sufficiently explored in clinical trials, including musculoskeletal adverse events (MAEs). Objective. To examine the association between use of PCSK9 inhibitors with and without concurrent statins and risk of MAEs. Patients and Methods. FDA Adverse Event Reporting System (FAERS) dataset of PCSK9 inhibitors and statins from October 2015 to June 2021 was queried. The reporting odds ratio (ROR) with relevant 95&#x0025; confidence interval (95&#x0025; CI) was calculated as the index of disproportionality. Outcome of MAEs of different PCSK9 inhibitors regimens was also investigated. Results. 3,185 cases of PCSK9 inhibitor-associated MAEs were recorded. PCSK9 inhibitor class alone demonstrated a strong link to MAEs (ROR 5.92; 95&#x0025; CI 5.70-6.15), and evolocumab was associated with more reports of MAEs than alirocumab. Concomitant use with statins leaded to an increased occurrence of MAEs (ROR 32.15 (25.55-40.46)), and the risk differed among different statins. The PCSK9 inhibitors were safer than statins in terms of hospitalization rate and death rate (15.64&#x0025; vs. 36.83&#x0025;; 0.72&#x0025; vs. 3.53&#x0025;). Conclusions. This pharmacovigilance investigation suggests that PCSK9 inhibitors are associated with MAEs. The risk significantly increases when combined with statins. Increased laboratory and clinical monitoring are required to timely diagnose and manage MAEs.

Lingqing Ding

Congqin Chen

Yongkuan Yang

Jie Fang

Longxing Cao

Yige Liu

Musculoskeletal Adverse Events Associated with PCSK9 Inhibitors: Disproportionality Analysis of the FDA Adverse Event Reporting System

Background. Pulmonary arterial hypertension (PAH) usually causes right ventricular dysfunction, which is closely related to cardiac fibrosis. But cardiac fibrosis mechanism remains unclear. Our purpose was to explore microRNA-325-3p (miR-325-3p)/human epididymis protein 4&#x2019;s (HE4) role in the occurrence and development of right ventricular fibrosis in PAH. Methods. The right ventricular fibrosis model of rats with PAH was constructed, and miR-325-3p was overexpressed to explore miR-325-3p&#x2019;s effect on myocardial fibrosis in rats with PAH. Pearson correlation coefficient examined the correlation between HE4 and miR-325-3p. We separated and identified the primary rat myocardial fibroblasts from the heart tissue. Then, the Ang II-treated myocardial fibroblast fibrosis model was constructed. miR-325-3p mimics and si-HE4 and oe-HE4 cell lines were constructed to investigate miR-325-3p and HE4 effects on myocardial cell fibrosis. Then, we added PI3K inhibitor LY294002 to study the effects of HE4 in cell fibrosis by the PI3K/AKT pathway. Starbase was used to predict miR-325-3p and HE4 binding sites. Dual-luciferase reporter assay verified whether miR-325-3p and HE4 were targeted. Results. Overexpression of miR-325-3p alleviated myocardial fibrosis in rats with PAH. Pearson correlation coefficient showed that HE4 was negatively correlated with miR-325-3p expression. Starbase predicted that miR-325-3p had binding sites with HE4. Dual-luciferase reporter assay demonstrated that miR-325-3p targeted HE4. Overexpression of miR-325-3p downregulated HE4 and inhibited myocardial fibroblast fibrosis. HE4 knockdown inhibited myocardial fibroblast fibrosis. HE4 promoted myocardial fibroblast fibrosis and activated the PI3K/AKT pathway. In addition, HE4 affected myocardial fibroblast fibrosis through the PI3K/AKT pathway. Conclusions. miR-325-3p could target HE4 to relieve right ventricular fibrosis in rats with PAH. This study could provide new targets and strategies for right ventricular fibrosis in PAH.

Yi Tang

Xiaowei Huo

Junyu Liu

Yijin Tang

Min Zhang

Wenlin Xie

Zhaofen Zheng

Jin He

Jiayan Lian

MicroRNA-325-3p Targets Human Epididymis Protein 4 to Relieve Right Ventricular Fibrosis in Rats with Pulmonary Arterial Hypertension

Background. To explore the application value of layered strain technique in non-ST elevation acute coronary syndrome (NSTE-ACS). Methods. 120 patients with suspected NSTE-ACS undergoing coronary angiography in our hospital from December 2018 to December 2019 were prospectively selected. According to the results of coronary angiography, the patients were divided into the significant CAD group and the nonsignificant CAD group. Echocardiography was performed 1-2 hours before invasive coronary angiography. The long axis and circumferential strain of the endocardium, myocardial layer, and epicardium were evaluated by the layered strain technique. The territorial longitudinal strain (TLS), the global longitudinal strain (GLS) of the three myocardial layers, and the global circumferential strain (GCS) were calculated based on the perfusion region of the three coronary arteries and the 17-segment model of the left ventricle. The primary endopoints were TLS and GCS of the three-layer myocardium. Results. Compared with the nonsignificant CAD patients, the TLS and GCS of three-layer myocardium in significant CAD patients were decreased, especially in the endocardium. The absolute values of TLS and GCS of the endocardium and epicardium in significant CAD patients were lower than those in nonsignificant CAD patients. This indicates a significant decrease in endocardial function. Receiver operating characteristic (ROC) curve analysis showed that endocardial TLS was superior to LVEF, Troponin I (TnI), and other strain parameters in evaluating the extent of coronary lesions. Conclusions. The layered strain technique of 2D-STE can evaluate the severity of coronary lesions in patients with NSTE-ACS, and for significant CAD patients, endocardial function is significantly more impaired than epicardial function.

Nan Zhao

Luyao Zhang

Xijun Zhang

Chuang Li

Yang Li

Peng Qian

Yu Lu

Application of Layered Strain Technique in NSTE-ACS

Pulmonary arterial hypertension (PAH) is characterized by abnormal remodeling of pulmonary vessel walls caused by excessive pulmonary arterial smooth muscle cell (PASMC) proliferation. Our previous clinical studies have demonstrated the importance of the downregulated circRNA in PAH. However, the role of upregulated circRNAs is still elusive. Here, we identified the upregulated circRNA in PAH patients, hsa_circWDR37_016 (circWDR37), as a key regulator of hypoxic proliferative disorder of pulmonary arterial smooth muscle cells (PASMCs). Quantitative real-time PCR (qRT-PCR) analysis validated that exposure to hypoxia markedly increased the circWDR37 level in cultured human PASMCs. As evidenced by flow cytometry, 5-ethynyl-2<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.04979992pt" id="M1" height="11.4859pt" version="1.1" viewBox="-0.0498162 -11.4361 3.89517 11.4859" width="3.89517pt"><g transform="matrix(.0091,0,0,-0.0091,0,-5.741)"><path id="g50-31" d="M310 541L304 571C290 586 211 619 185 610L80 76L131 52L310 541Z"/></g></svg>-deoxyuridine (EdU) incorporation, wound healing, and Tunel assay, silencing of endogenous circWDR37 attenuated proliferation and cell-cycle progression in hypoxia-exposed human PASMCs in vitro. Furthermore, bioinformatics and Luciferase assay showed that circWDR37 directly sponged hsa-miR-138-5p (miR-138) and was involved in the immunoregulatory and inflammatory processes of PAH. Together, these studies suggested new insights into circRNA regulated the pathology of PAH, providing a new potential therapeutic target for PAH treatment.

Shan-Shan Li

Shuang Liang

Yao Long

Xu Chen

Xin Jin

hsa_circWDR37_016 Regulates Hypoxia-Induced Proliferation of Pulmonary Arterial Smooth Muscle Cells

Hyperlipidemia characterized by abnormal deposition of cholesterol in arteries can cause atherosclerosis and coronary artery occlusion, leading to atherosclerotic coronary heart disease. The body prevents atherosclerosis by reverse cholesterol transport to mobilize and excrete cholesterol and other lipids. Apolipoprotein A1, the major component of high-density lipoprotein, plays a key role in reverse cholesterol transport. Here, we reviewed the role of apolipoprotein A1-targeting molecules in antiatherosclerosis therapy, in particular ATP-binding cassette transporter A1, lecithin-cholesterol acyltransferase, and scavenger receptor class B type 1.

Xiuting Xu

Zikai Song

Bao Mao

Guoliang Xu

Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives

Objective. Remote ischemic conditioning (RIC) is a cardioprotective method in ischemia/reperfusion (I/R) injury. This study investigated the mechanism of Rho-kinase-mediated autophagy in RIC. Methods. Sixty male Sprague&#x2013;Dawley rats were randomly divided into six groups: sham, I/R, RIC, I/R+fasudil, RIC+wortmannin, and RIC+fasudil+wortmannin. Throughout the experiment, mean arterial pressure and heart rate were continuously monitored. Histopathology and ultrastructure and myocardial enzymes&#x2019; expression were evaluated to determine the degree of cardiac injury. The protein expression of the Rho-kinase substrates myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1), autophagy-related protein light chain 3-II (LC3-II) and Beclin 1, and protein kinase B (AKT) was measured in the myocardial tissue. Results. Compared with the sham group, the mean arterial pressure and heart rate were decreased, myocardial enzyme levels were increased, and myocardial damage was aggravated in the I/R group; however, RIC improved these alterations. The expression of phosphorylated MLC and MYPT1 was lower, while LC3-II, Beclin 1, and phospho-AKT expression levels were higher in the RIC group compared with the I/R group. Obviously, treatment of the I/R group rats with fasudil, a Rho-kinase inhibitor, significantly ameliorated the I/R effects, whereas treatment of the RIC group rats with wortmannin, a phosphatidylinositol-3 kinase (PI3K) inhibitor, inhibited the RIC protective effects. Moreover, the rats in the RIC+fasudil+wortmannin group showed similar changes to those in the RIC+wortmannin group. Conclusion. These results showed that RIC protected the myocardium from I/R injury by suppressing Rho-kinase and the underlying mechanism may be related to enhancing autophagy via the PI3K/AKT pathway.

Jie Gao

Feng Min

Shasha Wang

Heng Lv

Huan Liang

Ben Cai

Xianjie Jia

Qin Gao

Ying Yu

Effect of Rho-Kinase and Autophagy on Remote Ischemic Conditioning-Induced Cardioprotection in Rat Myocardial Ischemia/Reperfusion Injury Model

Background. Chronic heart failure (CHF) is a serious heart disease resulting from cardiac dysfunction. Oxidative stress is an important factor in aging and disease. Butein, however, has antioxidant properties. To determine the effect of butein on oxidative stress injury in rats, a CHF rat model was established. Methods. The CHF rat model was induced by abdominal aortic coarctation (AAC). Rats in CHF+butein and sham+butein group were given 100&#x2009;mg/kg butein via gavage every day to detect the effect of butein on oxidative stress injury and myocardial dysfunction. The cardiac structural and functional parameters, including the left ventricular end-systolic dimension (LVESD), the left ventricular end-diastolic dimension (LVEDD), the left ventricular ejection fraction (LVEF), and the left ventricular fractional shortening (LVFS), were measured. Oxidative stress was measured through the production of reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA). Cardiac injury markers like creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) were evaluated. Hematoxylin and eosin (H&#x0026;E) staining was used to observe the myocardial cell morphology. The effect of butein on the extracellular signal-regulated kinase (ERK)/nuclear factor-E2 p45-related factor (Nrf2) signaling was confirmed by Western blot analysis. Results. Butein had a significant effect on CHF in animal models. In detail, butein inhibited oxidative stress, relieved cardiac injury, and alleviated myocardial dysfunction. Importantly, butein activated the ERK1/2 pathway, which contributed to Nrf2 activation and subsequent heme oxygenase-1 (HO-1) and glutathione cysteine ligase regulatory subunit (GCLC) induction. Conclusions. In this study, butein inhibits oxidative stress injury in CHF rat model via ERK/Nrf2 signaling pathway.

Peng Liu

Quanli Pan

Butein Inhibits Oxidative Stress Injury in Rats with Chronic Heart Failure via ERK/Nrf2 Signaling

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Cardiovascular Therapeutics publishes original research and review articles focusing on cardiovascular and clinical pharmacology, as well as clinical trials of novel cardiovascular therapies.

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Cardiovascular Therapeutics - Table of contents 2022

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Cardiovascular Therapeutics publishes original research and review articles focusing on cardiovascular and clinical pharmacology, as well as clinical trials of novel cardiovascular therapies.

Cardiovascular Therapeutics