Programmed Cell Death of Endothelial Cells in Myocardial Infarction and Its Potential Therapeutic Strategy

Wu, Mingyue; Huang, Zixia; Zeng, Lijin; Wang, Chunfei; Wang, Deming

doi:https://doi.org/10.1155/2022/6558060

Cardiology Research and Practice

On this page

Abstract Introduction Conclusions Data Availability Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Special Issue

Endothelial Injury and Repair in Coronary Heart Disease 2021

View this Special Issue

Review Article | Open Access

Volume 2022 | Article ID 6558060 | https://doi.org/10.1155/2022/6558060

Programmed Cell Death of Endothelial Cells in Myocardial Infarction and Its Potential Therapeutic Strategy

Mingyue Wu,¹Zixia Huang,¹Lijin Zeng,²Chunfei Wang,³and Deming Wang¹

Academic Editor: Jianqin Wei

Received17 Mar 2022

Accepted16 Apr 2022

Published11 May 2022

Abstract

Cardiovascular disease, especially coronary artery disease and stroke, kills around one-third of the world’s population, and myocardial infarction, a primary symptom of coronary heart disease, is a major worldwide health problem. Cardiovascular disease research has historically focused on promoting angiogenesis following myocardial damage. Myocardial vascular repair is crucial for improving myocardial infarction prognosis. Endothelial cells, the largest population of nonmyocytes within myocardial tissue, play an important role in angiogenesis. In recent years, different types of programmed cell death such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy have been described and found to be linked with cardiovascular diseases such as myocardial infarction, heart failure, and myocarditis. This will have important implications for reforming the treatment strategy of cardiovascular diseases. Different types of cell death of endothelial cells in myocardial infarction have been proposed, the roles and mechanisms of endothelial cell death in myocardial infarction are summarized in this review, and endothelial cell death inhibition as a therapeutic technique for treating myocardial infarction might be advantageous to human health.

1. Introduction

Myocardial infarction (MI) is defined as the death of myocardial cells due to insufficient myocardial perfusion, which can be caused by coronary occlusion or reduced blood flow, or by an acute supply-demand mismatch without coronary occlusion [1]. MI and subsequent heart failure are the leading causes of death in patients with coronary heart disease [2]. Perfusion of cardiac microvessels that is sustained and efficient is a significant element in avoiding cell death and extending the lifespan of injured myocardium following MI [3]. As the most nonmuscle cells in the heart, endothelial cells (ECs) play a crucial role in ischemic heart disease. The results of genetic lineage tracing revealed that newly formed capillaries after MI were generated by pre-existing ECs in the infarct marginal zone [4], and this process is facilitated by the clonal proliferation of resident ECs [3], and other cell sources have no bearing on angiogenesis.

Programmed cell death (PCD) was first used to describe cell death during insect development, and a similar process was subsequently found in humans and referred to as apoptosis. Programmed cell death is the process of removing unwanted, infected, or damaged cells and plays an important role in maintaining homeostasis of the body and host defense against pathogens. Unlike nonprogrammed cell lysis, programmed cell death is controlled by distinct signaling pathways, and these signaling pathways are cross-linked. Apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, and other kinds of PCD have all been found thus far. PCD is significant in the etiology of atherosclerosis [5], cardiovascular disease [6], and neurological disease [7]. The types of PCD of ECs in MI have been documented, but no comprehensive review has been published to date. The mechanism of distinct forms of ECs death is discussed in this review, as well as its importance in the potential therapy of MI.

2. Apoptosis

2.1. Overview of Apoptosis

Apoptosis, which is divided into two stages: the formation of apoptotic vesicles, and the phagocytosis and degradation of apoptotic vesicles by other cells, is a biological phenomenon first proposed by Kerr et al. [8], morphological changes such as chromatin coalescence and margination, followed by nuclear rupture, plasma membrane, or nuclear membrane wrapping broken DNA and organelles to form apoptotic vesicles, which can be quickly phagocytosed and therefore are mostly present in the cytoplasm of phagocytosed cells. Apoptosis is involved in the regulation of cell numbers in a variety of tissues, both physiologically and pathologically [8]. The intrinsic (also known as mitochondrial or Bcl-2-controlled) pathway and the extrinsic (also called death receptor) pathway both initiate apoptosis [9]. The nematode Caenorhabditis elegans expresses the human Bcl-2 gene, which decreases apoptosis [10], and ced-9 inhibits the function of ced-3 or ced-4, which has comparable effects to Bcl-2 [11]. The Bcl-2 homology 3 (BH3), Bcl-2-associated X protein (BAX), and Bcl-2 antagonist/killer (BAK), three functionally and physically separate subgroups of the Bcl-2 protein family, interact in the outer mitochondrial membrane and are seen as apoptosis switches. BAX and BAK produce oligomers that permeate the outer mitochondrial membrane when enough BH3-only proteins are triggered by various intracellular damages that surpass the apoptotic threshold, resulting in mitochondrial outer membrane permeabilization (MOMP) [12], which releases apoptotic factors into the cytoplasm, particularly cytochrome c [13, 14], and then, activation of caspase-9 on apoptosis activating factor 1 (APAF1) is thus promoted [15], APAF1 is homologous to ced-4 [13], and subsequent activation of caspase-3 and caspase-7 initiates the caspase cascade event, resulting in apoptosis [15, 16]. MOMP also promotes the production of second mitochondrial activator of caspases (SMAC) and HTRA serine peptidase 2 (HTR2), which both inhibit X-linked inhibitor of apoptosis (XIAP) [17] that inhibits the effector caspases [18] (Figure 1).

Figure 1

Molecular mechanisms of pyroptosis, apoptosis, and necroptosis and their network interactions. The intrinsic pathway of apoptosis (blue) is induced by the triggering of MOMP by BAX and BAK leading to cytochrome C activation and further activation of caspase-9 on APF1. Death receptor-mediated apoptosis requires the formation of a pro-apoptotic caspase-8 dimer, and both caspase-8 and caspase-9 promote the downstream executioner caspase-3 and caspase-7 activation, which induces apoptosis. Activation of death receptors similarly triggers necroptosis (orange). Activated RIPK3 phosphorylates and activates the executor of necroptosis, MLKL, which forms pores in the cell membrane, leading to cell lysis and the release of DAMPs. Cellular stress leads to inflammasome formation and activation of caspase-1 and cleavage of GSDMD, and cytokines such as IL-18 and IL-1β are released through the membrane pores formed by GSDMD-N and trigger pyroptosis (green).

Another mitochondrial change is the opening of the mitochondrial permeability transition pore (MPTP), which allows nonselective passage of ≤1.5 kD molecules and causes apoptosis when the mitochondrial matrix is under high osmotic pressure [19]. Outer membrane proteins (voltage-dependent anion channel, VDAC), intermembrane proteins, at least one inner membrane protein (the adenine nucleotide translocator, ANT), and at least one matrix protein (cyclophilin D) are known to be involved in the permeability transition [20–22]. It was found that mitochondria-targeted PT inducers do trigger apoptosis in thymocytes, which is also precluded by mitochondria-specific PT inhibitors such as bongkrekic acid (ligand of ANT) [23, 24].

Apoptosis can also be triggered by the death receptor pathway (Figure 1). Tumor necrosis factor receptor superfamily, such as TNFR1, Fas, CAR1, DR4, and DR5, are related to intracellular death structural domains via their ligands [25], encouraging the development of the death-inducing signaling complex (DISC) [26], activating caspase-8, and its downstream effector caspases (caspase-3 and caspase-7) [27]. Caspase-8 also cleaves Bid, a BH3-only protein, into tBid, a pro-apoptotic form that accumulates in mitochondria and stimulates cytochrome c release, causing apoptosis via the intrinsic pathway [28].

2.2. Therapeutic Strategies of Inhibiting Endothelial Cells Apoptosis and Improving the Myocardial Infarction

Apoptosis was shown to be 8-9 times higher in nonmyocytes than in myocytes in myocardial biopsies from individuals with ischemic cardiomyopathy, such as myocardial infarction, and 25% of these nonmyocytes were endothelial cells [29]. Increased amounts of mitochondrial reactive oxygen species accompany cardiac ischemia-reperfusion damage, which can lead to ECs apoptosis [30]. In the mini-swine model of AMI reperfusion, Fas and Bax overexpression or Bcl-2 low expression in the infarct region and marginal tissues plays a crucial role in accelerating ECs apoptosis at Day 7 [31].

Long noncoding RNAs (lncRNAs) are important regulators of cardiac remodeling. By suppressing the miR-26b-5p/Mfn1 pathway-mediated apoptosis of cardiac microvascular endothelial cells (CMECs) following MI, the lncRNA Malat1 plays a crucial role in microcirculation repair [32]. In ECs, the long noncoding ribonucleic acid-cardiac apoptosis-related (lncRNA-CARL) can reduce the expression of Bax and PHB2, decrease caspase-3 activity, and raise the amount of the anti-apoptotic protein Bcl-2 [33]. Knocking down the lncRNA KCNQ1OT1 (KCNQ1OT1) promotes CMECs proliferation in a mouse model of AMI, while inhibiting apoptosis and lowering inflammatory factor levels [34].

Extracellular vesicles (EVs) are naturally secreted nanovesicles that play a key role in stem cell-mediated cardioprotection, and exosome production from induced pluripotent stem cells (iPSCs)-EV improves the angiogenic and anti-apoptotic properties of cardiac endothelial cells when compared to iPSCs [35]. Exosomal EV-C-MSCsN1ICD from cardiac mesenchymal stem cells reduces ECs and cardiomyocyte apoptosis mediated by oxidative stress and ischemia injury [36]. Remote ischemic conditioning (RIC)-EV inhibits ECs apoptosis by Hsp70 [37]. In vitro, miRNA-21-loaded EVs successfully transfer miR21 to recipient cells and lower the amount of the pro-apoptotic protein PDCD4; in vivo, they prevent apoptosis in ECs in the ischemia marginal zone [38]. MiR-21 prevents CMECs damage following AMI via the PTEN/VEGF pathway, according to another research [39]. MiR-24 was found to be highly expressed in cardiac ECs and was increased considerably following MI. In mice, blocking miR-24 inhibited ECs apoptosis and reduced the size of MI [40]. MiR-17-5p downregulation raises the amount of the anti-apoptotic protein Bcl-2 and lowers the level of apoptotic protein (bax/caspase 3/caspase 9) in the heart, maintaining cardiac function after an AMI by slowing apoptosis and healing vascular damage [41]. Cdip1 silencing by exosomal miRNA-21-5p-targeting cardiac telocytes prevents CMECs apoptosis and increases angiogenesis after MI [42]. MiR-124 induces ECs apoptosis via the P38/MAPK and PI3K/AKT pathways and may be a contributing factor in vascular endothelial damage in AMI [43]. By targeting granzyme B, MiR-518a-5p can reduce hypoxia/reoxygenation (H/R)-induced apoptosis and cell damage in human umbilical vein endothelial cells (HUVECs) [44].

Alpha-antitrypsin (AAT) overexpression reduces vascular endothelial cell death and increases cell proliferation under H/R conditions via decreasing the Rac1/PAK/p38 signaling pathway and antioxidative stress [45]. Fibroblast growth factor (FGF) is expressed in ECs, and basic FGF inhibits CMECs apoptosis and promotes angiogenesis via HIF-1, reducing myocardial injury [46]. CXCR7 activation has a protective impact on hypoxic ECs, reducing apoptosis, and promoting angiogenesis [47]. Under hypoxic circumstances, foxo3-mediated autophagy enhances CMECs apoptosis, which is a key pathophysiological cause of MI [48].

In addition, clinical trials have shown that the circulating apoptotic markers soluble TNF receptor 1 (sTNFR1) and sTNFR2 were found to be associated with myocardial infarct size and left ventricular insufficiency in patients with ST-segment elevation myocardial infarction (STEMI), suggesting that apoptosis may be a key determinant of the extent of I/R injury [49]. Perindopril is a third-generation angiotensin-converting enzyme inhibitor, which significantly reduces ECs apoptosis and improves abnormal ECs function in patients with MI [50]. Perindopril also reduces the pro-apoptotic effect of serum on ECs and promotes ECs renewal in patients with acute coronary syndrome [51]. The above studies suggest that therapeutic strategies targeting apoptosis have a wide range of clinical applications in myocardial infarction.

3. Necroptosis

3.1. Overview of Necroptosis

Necroptosis is a form of programmed death activated when apoptosis is inhibited, which is independent of caspase family activation pathways and can cause inflammatory responses. This process involves the activation and phosphorylation of receptor-interacting serine-threonine kinase 3 (RIPK3), which activates the pseudokinase mixed lineage kinase domain-like protein (MLKL), the final effector in necroptosis [52, 53] (Figure 1). This process promotes the release of damage-associated molecular patterns (DAMPs), which trigger inflammatory responses and the activation of pyroptosis [54, 55], as well as the efflux of pathogen-associated molecular patterns (PAMPs) [56] in the context of cellular infection, which triggers an inflammatory response. Multiple innate immune signaling pathways, including those mediated by activation of TLRs, death receptors, and RIG-I-like receptors, can cause necroptosis [57]. RIPK1’s kinase activity is important in death receptor-induced necroptosis [58–60], and RIPK1 facilitates canonical necroptosis signaling when cell surface TNF binds to TNF receptor 1 (TNFR1) transduces and autophosphorylates RIPK1. Direct inhibitors of RIPK1, necrostatins, can block this pathway [57]. Intervention in the cell membrane repair process involving the ESCRT-III protein complex appears to interrupt or even prevent cell death in the early stages of MLKL activation [61]. Caspase-8 suppresses necroptosis mediated by RIPK3 and MLKL as well as acting as the starting caspase of exogenous apoptosis. The cleavage of RIPK1 by caspase-8 is a critical step in the decomposition of the death-inducing complex. TNF-induced aberrant cell death can be reduced by Asp325 of RIPK1 [62].

3.2. Therapeutic Strategies of Inhibiting Endothelial Cells Necroptosis and Improving the Myocardial Infarction

In CMECs, RIPK3 levels and mPTP opening rates were considerably elevated after H/R damage. Ischemia/reperfusion (I/R) injury can also activate RIPK3; however, melatonin reduces mPTP opening and prevents CMECs necroptosis after cardiac I/R injury by inhibiting the RIPK3-PGAM5-CypD signaling pathway [63]. Baicalin, a compound derived from scutellaria baicalensis, inhibits the production of the proteins RIP1, RIP3, and p-MLKL, preventing necroptosis in CMECs following H/R injury [64]. Overexpression of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) protects I/R-treated CMECs by preventing aberrant mPTP opening and suppressing the necroptosis signaling pathway [65]. These findings imply that inhibiting necroptosis could be a useful therapeutic method for treating endothelial damage following MI.

4. Pyroptosis

4.1. Overview of Pyroptosis

The caspase-1-mediated canonical route and the caspase-4/5/11-mediated noncanonical pathway may both initiate pyroptosis [66, 67]. The caspase-1 pathway is vital in innate immunity, and the inflammasome complex signals the downstream adaptor ASC or NLRC4 to activate the caspase-1 molecule when particular stimulatory signals are detected [68], such as bacteria, viruses, and toxins [69]. The AIM2/ASC inflammasome is the most well-known, as it identifies cytoplasmic double-stranded DNA linked to AIM2; the NLRP3/ASC inflammasome is triggered by diverse membrane-damaging chemicals; the Pyrin/ASC inflammasome indirectly senses bacterial toxins inactivating host Rho GTPases; and the NAIP/NLRC4 acts as a receptor and signal amplifier for direct recognition of flagellin and type III secretion system on bacteria, respectively. The caspase-4/5/11 pathway is activated when lipopolysaccharide (LPS) is detected in the cytoplasm. The roles of caspase-4 and caspase-5 in humans are similar. Murine caspase-11 is located adjacent to caspase-1 on chromosome position, a receptor for cytoplasmic lipopolysaccharide, and a homolog of human caspase-4. Caspase-11 deletion protects mice from endotoxic shock as compared to caspase-1 deletion [70]. Caspase-4/5/11 bind directly to cytoplasmic LPS to initiate pyroptosis, and CARD on caspases mediates this binding [71]. Furthermore, Pannexin-1 channels, purinergic P2X7 pore [72], and high mobility group protein B1 (HMGB1) [73] are required for caspase-11-mediated pyroptosis and endotoxin shock [72], a mechanism that seems to be independent of TLR4 [74]. Heparin inhibits cytoplasmic transport of LPS and caspase-11 activation by reducing HMGB1-LPS interactions and glycocalyx breakdown in macrophages [75]. GSDMD is cleaved into the GSDMD-N-terminal and GSDMD-C-terminal when caspase-1 and caspase-4/5/11 are activated. The N-terminus of GSDMD is carried to the plasma membrane, where it homo-oligomerizes to form a 10- to 15-nm pore [76, 77]. This pore promotes rapid cell enlargement and membrane rupture, allowing IL-18, IL-1β, and HMGB1 to be released [73, 78] (Figure 1). Recent research has found that cell membrane rupture is not required for cytokine release and that IL-1β may be released from live cells, indicating that GSDMD might have a role in cytokine release without triggering pyroptosis [79–81]. GSDMD pores provide reasonable channels for the release of IL-1β (4.5 nm in diameter) and IL-18 (5.0 nm in diameter) [82]. In both mouse and human models, IL-1β secretion through GSDMD membrane pores has been observed [81, 83, 84], and GSDMD loss lowers IL-1β secretion [85].

4.2. Therapeutic Strategies of Inhibiting Endothelial Cells Pyroptosis and Improving the Myocardial Infarction

After myocardial infarction, ASC speck formation was observed in mouse cardiac ECs, suggesting that endothelial NLRP3 inflammasomes may play a role in MI. NLRP3 inflammasomes are involved in IL-1β release and pyroptosis in endothelial cells and cardiac fibroblasts [86]. Bean1 overexpression resulted in a large rise in NLRP3 and IL-1β in CMECs following MI damage [87], suggesting that Bean1 may serve as a therapeutic target for NLRP3-mediated vascular injury in the treatment of MI. Ventricular remodeling is a critical link in the evolution of MI into heart failure, and it is suggested that NLRP3 inflammasome also plays a significant role in the process of ventricular remodeling following MI [88]. Furthermore, by lowering vascular endothelial cell pyroptosis, chitosan hydrogel increases the efficiency of bone marrow mesenchymal stem cells in the treatment of MI [89]. The above evidence suggests that means of inhibiting ECs pyroptosis need to be discovered and applied in the treatment of MI.

5. Ferroptosis

5.1. Overview of Ferroptosis

Oxidative stress and lipid peroxidation are key determinants of cell fate, and iron-dependent lethal lipid peroxidation drives ferroptosis [90]. Glutathione peroxidase 4 (GPX4) is a selenoprotein that was discovered to cause nonapoptotic cell death due to lipid peroxidation long before the concept of ferroptosis was proposed [91]. Ferroptosis is thought to be aided by the system xc⁻-GSH-GPX4 pathway [90], with glutathione (GSH) depletion and reduced GPX4 activity affecting the metabolic process of lipid oxides, boosting the generation of reactive oxygen species (ROS) by Fe²⁺, and so inducing ferroptosis. Phospholipid hydroperoxides (PLOOHs) are major executors of ferroptosis, and GPX4 acts as a neutralizing enzyme for PLOOH, converting PLOOH to PLOH [92]. Erastin and RSL3 act as inhibitors of system xc⁻ and GPX4 to trigger ferroptosis, RSL3 directly inactivates GPX4, and erastin inhibits cystine input, reducing cysteine in glutathione GSH synthesis, indirectly reducing GPX4 production, and causing the accumulation of PLOOHs, which will lead to lipid excess. Oxidation products and an increase in oxidatively changed proteins further compromise cell membrane integrity, resulting in cell death. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a key driver of ferroptosis. Polyunsaturated fatty acids (PUFA) are the precursors of PLOOHs. ACSL4 catalyzes the linking of free PUFA with coenzyme A to generate PUFA-CoA, which is then esterified under the catalysis of LPCAT3 and forms PUFA-PL with PL. PUFA-PL is prone to peroxidation in the condition of rich iron and ROS. This accumulation of lipid peroxides in the cell membrane eventually destroys the integrity of the membrane, resulting in ferroptosis. ACSL4 depletion or inhibition drastically transforms the long-chain PUFA tails in phospholipids to short-chain or monounsaturated fatty acid (MUFA) tails [93, 94], determining ferroptosis sensitivity [95]. Ferritin heavy chain 1 (FTH1) is involved in ferritin phagocytosis and ferroptosis, and the cargo receptor NCOA4 detects and binds to FTH1 and transports iron-bound ferritin to autophagosome, a selective autophagy form, completing ferritin breakdown, and iron release [96, 97].

5.2. Therapeutic Strategies of Inhibiting Endothelial Cells Ferroptosis and Improving the Myocardial Infarction

Ferroptosis has been linked to the development of cardiovascular diseases [98], tumors [99], metabolic diseases [100], neurological diseases [101], and inflammatory and immunological diseases [102] in recent investigations, and ferroptosis has also been detected in cardiomyocytes from mice with MI [103]. However, ferroptosis has rarely been reported in endothelial cells of MI. Using biological information technology, Yifan et al. [104] screened the differential expression of ferroptosis-related genes in circulating endothelial cells of patients with AMI. These genes included C-X-C motif ligand 2 (CXCL2), FTH1, toll-like receptor 4 (TLR4), JUN (AP-1 transcription factor subunit), endothelial PAS domain protein 1 (EPAS1), DNA damage-inducible transcript 3 (DDIT3), Jun dimerization protein 2 (JDP2), activating transcription factor 3 (ATF3), were considerably overexpressed in the AMI group, showing that ferroptosis is involved in the control of metabolism in the circulating EC of AMI patients. This lays the groundwork for future research into the pathophysiology of ferroptosis in AMI patients.

6. Autophagy

6.1. Overview of Autophagy

Autophagy is a highly conserved adaptive mechanism that helps keep cells in a state of homeostasis. Macroautophagy, microautophagy, and chaperone-mediated autophagy [105] are three subtypes of autophagy that all entail the breakdown of cellular contents in lysosomes; however, the methods are distinct. The most common kind is macroautophagy. Macroautophagy was formerly thought to be a nonselective process, but it has now been found to selectively degrade intracellular microorganisms, damaged lysosomes, and mitochondria [106, 107]. Under cellular stress circumstances such as food restriction, oxidative stress, protein aggregation, and hypoxia, autophagy is triggered, and stress signaling pathways are mainly focused on the ULK1 complex, which is made up of four proteins, ATG101, ATG13, ULK1, and FIP200 [108]. PI3KC3 complex I, which is sorted by class III PI3K, vacuolar protein 34 (VPS34), Beclin 1, ATG14, activating molecules in Beclin 1-regulated autophagy protein 1 (AMBRA1), and a general vesicle transporter (p115), initiates phagophore nucleation [109], then comes phagophore expansion, which requires the binding of membrane-resident phosphatidylethanolamine by Ub-like Atg8 family proteins such microtubule-associated protein light chain 3 (LC3) protein and γ-aminobutyric acid receptor-associated protein (GABARAPs) [109]. Finally, autophagosomes are formed when a portion of the cytoplasm is phagocytosed to form double-membrane vesicles known as autophagosomes. After autophagosome maturation, the autophagosome outer membrane combines with lysosomes to produce autophagolysosomes, and the contents of the autophagosome are degraded and recycled [110].

6.2. Therapeutic Strategies of Inhibiting Endothelial Cells Autophagy and Improving the Myocardial Infarction

Autophagy sheds light on new therapeutic targets in the myocardial infarction. VEGF-A, ROS, GRP78/Bip, and LC3-II/LC3-I expression levels in the vascular ECs of MI mice were considerably enhanced, and VEGF-A promotes angiogenesis after AMI via the ROS-ER-autophagy axis [111]. In the injured myocardium of zebrafish, autophagy was also discovered, and metformin increased autophagic flux; caused endocardial, epicardial, and endothelial regeneration; and accelerated MI cell proliferation. When autophagic flow was stopped, however, all of these effects were delayed [112]. Angiogenic factor 1 (AGGF1) is an angiogenic factor that activates JNK in endothelial cells, causing autophagy and the formation of the Becn1-Vps34-Atg14 complex, and therapy with Aggf1 protein can greatly enhance heart function after MI [113]. Moreover, transplanted mesenchymal stem cells (MSCs) generate apoptotic bodies (Abs), which stimulate lysosomal activity and enhance the expression of transcription factor EB (TFEB), a lysosome master gene for biogenesis and autophagy, in a MI model. Following a myocardial infarction, elevated TFEB boosted the expression of autophagy-related genes in ECs, boosting angiogenesis, and cardiac function recovery [114]. To attenuate I/R-induced cardiac damage, exosomal LINC00174 derived from vascular ECs suppressed p53-mediated autophagy [115]. AMI patients exhibited considerably greater levels of sTREM-1 and significantly lower levels of Sirt6, compared to healthy controls, and Sirt6-induced autophagy was observed to restrict TREM-1-mediated pyroptosis in ECs treated with oxidatively modified low-density lipoprotein (ox-LDL) [116]. The development of drugs that enhance autophagic flow would be a potential therapeutic strategy to improve the prognosis of MI.

7. Cross-Talk between Apoptosis, Necroptosis, Pyroptosis, Ferroptosis, and Autophagy

It was speculated that inhibition of caspase-8 and its adapter FADD would prevent apoptosis induced by the death receptor pathway, leading to an increase in cell numbers. However, this was not the case, and the study found that necroptosis was activated after caspase 8 [117] and FADD [118] were inhibited, which is the first time that the possibility of functional intertwining of different programmed cell deaths was identified [119, 120]. Necroptosis may be a means to kill damaged cells that have evaded apoptosis. Caspase-8 not only plays an important role in apoptosis and necroptosis, but also is able to regulate pyroptosis. Procaspase-8 inactivation also leads to ASC spot production, which promotes caspase-1 activation and subsequent GSDMD lysis and pyroptosis [121]. In the later stages of apoptosis, a decrease in intracellular K⁺ concentration leads to the activation of NLRP3 inflammasome and the onset of pyroptosis [122]. Notably, cells lacking caspase 1 or GSDMD still die due to NLRC4 activation, and this death is morphologically characteristic of apoptosis [123] and involves caspase 8, which can bind to ASC or NLRC4 [124, 125]. This suggests that in the absence of GSDMD, sustained inflammasome activation, although not inducing pyroptosis, leads to apoptotic forms of cell death. Alternatively, inflammasome activation can trigger apoptosis via caspase-1 or caspase-8-mediated processing of the BH3-only protein BID into a pro-apoptotic tBID, followed by activation of BAX/BAK and induction of MOMP via the intrinsic pathway [126, 127] (Figure 1). We know that both active MLKL and GSDMD may lead to membrane damage and that MLKL-dependent K⁺ spillover leads to NLRP3 activation [128]. Ferroptosis is a ferritin-degrading autophagy-dependent process [129], and it has been reported that knockdown or knockout of ATG5 and ATG7 can prevent iron death induced by the ferroptosis-inducer erastin by reducing intracellular iron levels and lipid peroxidation [130]. In addition, autophagy can reduce intracellular GSH levels [131], so the use of autophagy inhibitors can prevent the occurrence of GSH depletion-dependent ferroptosis [132]. This indicates that autophagy plays an important role in ferroptosis.

8. Conclusions

As summarized herein, apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy are all seen in endothelial cells following myocardial infarction. The majority of current research focuses on a single kind of cell death, despite the fact that many types of cell death have interconnected effects [133]. Cross-talk between different modes of endothelial cell death in myocardial infarction will be an area of ongoing interest, and it is unclear whether cell death is a direct cause or a key factor in the development of disease, or a consequence of disease-induced injury, and the extent to which therapeutic strategies targeting cell death can alleviate disease remains to be explored. With a better understanding of the different cell death modalities, more research focusing on the role of endothelial cell death in the pathogenesis of myocardial infarction is needed in the future, thus providing more possibilities for the treatment of myocardial infarction.

Data Availability

No data were used to support this study.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Mingyue Wu and Zixia Huang contributed equally to the paper.

References

J. A. De Lemos, L. K. Newby, and N. L. Mills, “A proposal for modest revision of the definition of type 1 and type 2 myocardial infarction,” Circulation, vol. 140, no. 22, pp. 1773–1775, 2019.
View at: Publisher Site | Google Scholar
G. K. Hansson, “Inflammation, atherosclerosis, and coronary artery disease,” New England Journal of Medicine, vol. 352, no. 16, pp. 1685–1695, 2005.
View at: Publisher Site | Google Scholar
D. Rohde and M. Nahrendorf, “Clonal and diverse: revisiting cardiac endothelial cells after myocardial infarction,” European Heart Journal, vol. 40, no. 30, pp. 2521-2522, 2019.
View at: Publisher Site | Google Scholar
L. He, X. Huang, O. Kanisicak et al., “Preexisting endothelial cells mediate cardiac neovascularization after injury,” Journal of Clinical Investigation, vol. 127, no. 8, pp. 2968–2981, 2017.
View at: Publisher Site | Google Scholar
L. Lin, M. X. Zhang, L. Zhang, D. Zhang, C. Li, and Y. L. Li, “Autophagy, pyroptosis, and ferroptosis: new regulatory mechanisms for atherosclerosis,” Frontiers in Cell and Developmental Biology, vol. 9, Article ID 809955, 2021.
View at: Publisher Site | Google Scholar
P. Patel and J. Karch, “Regulation of cell death in the cardiovascular system,” Cell Death Regulation in Health and Disease—Part C, vol. 353, pp. 153–209, 2020.
View at: Publisher Site | Google Scholar
D. Moujalled, A. Strasser, and J. R. Liddell, “Molecular mechanisms of cell death in neurological diseases,” Cell Death & Differentiation, vol. 28, no. 7, pp. 2029–2044, 2021.
View at: Publisher Site | Google Scholar
J. F. R. Kerr, A. H. Wyllie, and A. R. Currie, “Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics,” British Journal of Cancer, vol. 26, no. 4, pp. 239–257, 1972.
View at: Publisher Site | Google Scholar
D. R. Green, “Apoptotic pathways: paper wraps stone blunts scissors,” Cell, vol. 102, no. 1, pp. 1–4, 2000.
View at: Publisher Site | Google Scholar
D. L. Vaux, I. L. Weissman, and S. K. Kim, “Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2,” Science, vol. 258, no. 5090, pp. 1955–1957, 1992.
View at: Publisher Site | Google Scholar
J. Y. Yuan and H. R. Horvitz, “The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death,” Developmental Biology, vol. 138, no. 1, pp. 33–41, 1990.
View at: Publisher Site | Google Scholar
K. L. O’neill, K. Huang, J. Zhang, Y. Chen, and X. Luo, “Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane,” Genes & Development, vol. 30, no. 8, pp. 973–988, 2016.
View at: Publisher Site | Google Scholar
H. Zou, W. J. Henzel, X. Liu, A. Lutschg, and X. Wang, “Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c–dependent activation of caspase-3,” Cell, vol. 90, no. 3, pp. 405–413, 1997.
View at: Publisher Site | Google Scholar
R. M. Kluck, E. Bossy-Wetzel, D. R. Green, and D. D. Newmeyer, “The release of cytochrome c from mitochondria: a primary site for bcl-2 regulation of apoptosis,” Science, vol. 275, no. 5303, pp. 1132–1136, 1997.
View at: Publisher Site | Google Scholar
P. Li, D. Nijhawan, I. Budihardjo et al., “Cytochrome c and dATP-dependent formation of apaf-1/caspase-9 complex initiates an apoptotic protease cascade,” Cell, vol. 91, no. 4, pp. 479–489, 1997.
View at: Publisher Site | Google Scholar
G. S. Salvesen and V. M. Dixit, “Caspase activation: the induced-proximity model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 20, pp. 10964–10967, 1999.
View at: Publisher Site | Google Scholar
P. G. Ekert and D. L. Vaux, “The mitochondrial death squad: hardened killers or innocent bystanders?” Current Opinion in Cell Biology, vol. 17, no. 6, pp. 626–630, 2005.
View at: Publisher Site | Google Scholar
S. Galban and C. S. Duckett, “XIAP as a ubiquitin ligase in cellular signaling,” Cell Death & Differentiation, vol. 17, no. 1, pp. 54–60, 2010.
View at: Publisher Site | Google Scholar
T. Hirsch, I. Marzo, and G. Kroemer, “Role of the mitochondrial permeability transition pore in apoptosis,” Bioscience Reports, vol. 17, no. 1, pp. 67–76, 1997.
View at: Publisher Site | Google Scholar
M. W. Mcenery, A. M. Snowman, R. R. Trifiletti, and S. H. Snyder, “Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 8, pp. 3170–3174, 1992.
View at: Publisher Site | Google Scholar
N. Brustovetsky and M. Klingenberg, “Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2⁺,” Biochemistry, vol. 35, no. 26, pp. 8483–8488, 1996.
View at: Publisher Site | Google Scholar
G. Beutner, A. Ruck, B. Riede, W. Welte, and D. Brdiczka, “Complexes between kinases, mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore,” FEBS Letters, vol. 396, pp. 189–195, 1996.
View at: Publisher Site | Google Scholar
N. Zamzami, S. A. Susin, P. Marchetti et al., “Mitochondrial control of nuclear apoptosis,” Journal of Experimental Medicine, vol. 183, no. 4, pp. 1533–1544, 1996.
View at: Publisher Site | Google Scholar
P. Marchetti, T. Hirsch, N. Zamzami et al., “Mitochondrial permeability transition triggers lymphocyte apoptosis,” The Journal of Immunology, vol. 157, no. 11, pp. 4830–4836, 1996.
View at: Google Scholar
A. Ashkenazi and V. M. Dixit, “Death receptors: signaling and modulation,” Science, vol. 281, no. 5381, pp. 1305–1308, 1998.
View at: Publisher Site | Google Scholar
F. C. Kischkel, S. Hellbardt, I. Behrmann et al., “Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor,” The EMBO Journal, vol. 14, no. 22, pp. 5579–5588, 1995.
View at: Publisher Site | Google Scholar
S. Fulda and K. M. Debatin, “Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy,” Oncogene, vol. 25, no. 34, pp. 4798–4811, 2006.
View at: Publisher Site | Google Scholar
L. P. Billen, A. Shamas-Din, and D. W. Andrews, “Bid: a bax-like BH3 protein,” Oncogene, vol. 27, pp. S93–S104, 2008.
View at: Publisher Site | Google Scholar
M. Park, Y. T. Shen, V. Gaussin et al., “Apoptosis predominates in nonmyocytes in heart failure,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 297, no. 2, pp. H785–H791, 2009.
View at: Publisher Site | Google Scholar
J. Wang, S. Toan, and H. Zhou, “New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury,” Angiogenesis, vol. 23, no. 3, pp. 299–314, 2020.
View at: Publisher Site | Google Scholar
S. Kang, Y. J. Yang, Y. L. Wu, Yt Chen, L. Li, and Y. Tian, “Myocardium and microvessel endothelium apoptosis at day 7 following reperfused acute myocardial infarction,” Microvascular Research, vol. 79, no. 1, pp. 70–79, 2010.
View at: Publisher Site | Google Scholar
Y. Chen, S. Li, Y. Zhang et al., “The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics,” Redox Biology, vol. 41, Article ID 101910, 2021.
View at: Publisher Site | Google Scholar
L. Li, J. J. Wang, and H. S. Zhang, “LncRNA-CARl in a rat model of myocardial infarction,” European Review for Medical and Pharmacological Sciences, vol. 22, no. 13, pp. 4332–4340, 2018.
View at: Publisher Site | Google Scholar
Y. Wang, X. Yang, A. Jiang, W. Wang, J. Li, and J. Wen, “Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction,” The FASEB Journal, vol. 33, no. 12, pp. 13145–13160, 2019.
View at: Publisher Site | Google Scholar
M. Adamiak, G. Cheng, S. Bobis-Wozowicz et al., “Induced pluripotent stem cell (iPSC)–derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs,” Circulation Research, vol. 122, no. 2, pp. 296–309, 2018.
View at: Publisher Site | Google Scholar
W. Xuan, M. Khan, and M. Ashraf, “Extracellular vesicles from notch activated cardiac mesenchymal stem cells promote myocyte proliferation and neovasculogenesis,” Frontiers in Cell and Developmental Biology, vol. 8, p. 11, 2020.
View at: Publisher Site | Google Scholar
Q. Chen, M. Huang, J. Wu, Q. Jiang, and X. Zheng, “Exosomes isolated from the plasma of remote ischemic conditioning rats improved cardiac function and angiogenesis after myocardial infarction through targeting Hsp70,” Aging (Albany NY), vol. 12, no. 4, pp. 3682–3693, 2020.
View at: Publisher Site | Google Scholar
Y. Song, C. Zhang, J. Zhang et al., “Localized injection of miRNA-21-enriched extracellular vesicles effectively restores cardiac function after myocardial infarction,” Theranostics, vol. 9, no. 8, pp. 2346–2360, 2019.
View at: Publisher Site | Google Scholar
F. Yang, W. Liu, X. Yan et al., “Effects of mir-21 on cardiac microvascular endothelial cells after acute myocardial infarction in rats: role of phosphatase and tensin homolog (PTEN)/vascular endothelial growth factor (VEGF) signal pathway,” Medical Science Monitor, vol. 22, pp. 3562–3575, 2016.
View at: Publisher Site | Google Scholar
J. Fiedler, V. Jazbutyte, B. C. Kirchmaier et al., “MicroRNA-24 regulates vascularity after myocardial infarction,” Circulation, vol. 124, no. 6, pp. 720–730, 2011.
View at: Publisher Site | Google Scholar
S. Yang, T. Fan, Q. Hu et al., “Downregulation of microRNA-17-5p improves cardiac function after myocardial infarction via attenuation of apoptosis in endothelial cells,” Molecular Genetics and Genomics, vol. 293, no. 4, pp. 883–894, 2018.
View at: Publisher Site | Google Scholar
Z. Liao, Y. Chen, C. Duan et al., “Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction,” Theranostics, vol. 11, no. 1, pp. 268–291, 2021.
View at: Publisher Site | Google Scholar
V. Vallon and S. Verma, “Effects of SGLT2 inhibitors on kidney and cardiovascular function,” Annual Review of Physiology, vol. 83, no. 1, pp. 503–528, 2021.
View at: Publisher Site | Google Scholar
H. Yang, J. Su, W. Meng, X. Chen, Y. Xu, and B. Sun, “MiR-518a-5p targets GZMB to extenuate vascular endothelial cell injury induced by hypoxia-reoxygenation and thereby improves myocardial ischemia,” International Heart Journal, vol. 62, no. 3, pp. 658–665, 2021.
View at: Publisher Site | Google Scholar
Y. Feng, L. Hu, Q. Xu et al., “Cytoprotective role of alpha-1 antitrypsin in vascular endothelial cell under hypoxia/reoxygenation condition,” Journal of Cardiovascular Pharmacology, vol. 66, no. 1, pp. 96–107, 2015.
View at: Publisher Site | Google Scholar
Z. Rao, D. Shen, J. Chen et al., “Basic fibroblast growth factor attenuates injury in myocardial infarction by enhancing hypoxia-inducible factor-1 alpha accumulation,” Frontiers in Pharmacology, vol. 11, p. 1193, 2020.
View at: Publisher Site | Google Scholar
S. Zhang, J. Yue, Z. Ge, Y. Xie, M. Zhang, and L. Jiang, “Activation of CXCR7 alleviates cardiac insufficiency after myocardial infarction by promoting angiogenesis and reducing apoptosis,” Biomedicine & Pharmacotherapy, vol. 127, Article ID 110168, 2020.
View at: Publisher Site | Google Scholar
R. Wang, Q. Yang, X. Wang et al., “FoxO3α-mediated autophagy contributes to apoptosis in cardiac microvascular endothelial cells under hypoxia,” Microvascular Research, vol. 104, pp. 23–31, 2016.
View at: Publisher Site | Google Scholar
L. Nilsson, A. Szymanowski, E. Swahn, and L. Jonasson, “Soluble TNF receptors are associated with infarct size and ventricular dysfunction in ST-elevation myocardial infarction,” PLoS One, vol. 8, no. 2, Article ID e55477, 2013.
View at: Publisher Site | Google Scholar
C. Ceconi, K. M. Fox, W. J. Remme et al., “ACE inhibition with perindopril and endothelial function. results of a substudy of the EUROPA study: pertinent,” Cardiovascular Research, vol. 73, no. 1, pp. 237–246, 2007.
View at: Publisher Site | Google Scholar
E. Cangiano, J. Marchesini, G. Campo et al., “ACE inhibition modulates endothelial apoptosis and renewal via endothelial progenitor cells in patients with acute coronary syndromes,” American Journal of Cardiovascular Drugs, vol. 11, no. 3, pp. 189–198, 2011.
View at: Publisher Site | Google Scholar
L. Sun, H. Wang, Z. Wang et al., “Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase,” Cell, vol. 148, no. 1-2, pp. 213–227, 2012.
View at: Publisher Site | Google Scholar
J. M. Murphy, P. E. Czabotar, J. M. Hildebrand et al., “The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism,” Immunity, vol. 39, no. 3, pp. 443–453, 2013.
View at: Publisher Site | Google Scholar
L. S. Huang, Z. Hong, W. Wu et al., “mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury,” Immunity, vol. 52, no. 3, pp. 475–486 e5, 2020.
View at: Publisher Site | Google Scholar
S. Nystrom, D. J. Antoine, P. Lundback et al., “TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis,” The EMBO Journal, vol. 32, no. 1, pp. 86–99, 2012.
View at: Publisher Site | Google Scholar
A. L. Samson, Y. Zhang, N. D. Geoghegan et al., “MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis,” Nature Communications, vol. 11, no. 1, p. 3151, 2020.
View at: Publisher Site | Google Scholar
K. Newton and G. Manning, “Necroptosis and inflammation,” Annual Review of Biochemistry, vol. 85, no. 1, pp. 743–763, 2016.
View at: Publisher Site | Google Scholar
A. Degterev, J. Hitomi, M. Germscheid et al., “Identification of RIP1 kinase as a specific cellular target of necrostatins,” Nature Chemical Biology, vol. 4, no. 5, pp. 313–321, 2008.
View at: Publisher Site | Google Scholar
N. Holler, R. Zaru, O. Micheau et al., “Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule,” Nature Immunology, vol. 1, no. 6, pp. 489–495, 2000.
View at: Publisher Site | Google Scholar
Y. S. Cho, S. Challa, D. Moquin et al., “Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation,” Cell, vol. 137, no. 6, pp. 1112–1123, 2009.
View at: Publisher Site | Google Scholar
Y. N. Gong, C. Guy, H. Olauson et al., “ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences,” Cell, vol. 169, no. 2, pp. 286–300, 2017.
View at: Google Scholar
K. Newton, K. E. Wickliffe, D. L. Dugger et al., “Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis,” Nature, vol. 574, no. 7778, pp. 428–431, 2019.
View at: Publisher Site | Google Scholar
H. Zhou, D. Li, P. Zhu et al., “Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury,” Journal of Pineal Research, vol. 65, no. 3, Article ID e12503, 2018.
View at: Publisher Site | Google Scholar
J. Bai, Q. Wang, J. Qi et al., “Promoting effect of baicalin on nitric oxide production in CMECs via activating the PI3K-AKT-eNOS pathway attenuates myocardial ischemia-reperfusion injury,” Phytomedicine, vol. 63, Article ID 153035, 2019.
View at: Publisher Site | Google Scholar
Z. Zhou, H. He, K. Wang et al., “Granzyme a from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells,” Science, vol. 368, no. 6494, 2020.
View at: Google Scholar
C. Jia, H. Chen, J. Zhang et al., “Role of pyroptosis in cardiovascular diseases,” International Immunopharmacology, vol. 67, pp. 311–318, 2019.
View at: Publisher Site | Google Scholar
Y. J. Xu, L. Zheng, Y. W. Hu, and Q. Wang, “Pyroptosis and its relationship to atherosclerosis,” Clinica Chimica Acta, vol. 476, pp. 28–37, 2018.
View at: Publisher Site | Google Scholar
J. Shi, W. Gao, and F. Shao, “Pyroptosis: gasdermin-mediated programmed necrotic cell death,” Trends in Biochemical Sciences, vol. 42, no. 4, pp. 245–254, 2017.
View at: Publisher Site | Google Scholar
P. Broz and V. M. Dixit, “Inflammasomes: mechanism of assembly, regulation and signalling,” Nature Reviews Immunology, vol. 16, no. 7, pp. 407–420, 2016.
View at: Publisher Site | Google Scholar
N. Kayagaki, S. Warming, M. Lamkanfi et al., “Non-canonical inflammasome activation targets caspase-11,” Nature, vol. 479, no. 7371, pp. 117–121, 2011.
View at: Publisher Site | Google Scholar
J. Shi, Y. Zhao, Y. Wang et al., “Inflammatory caspases are innate immune receptors for intracellular LPS,” Nature, vol. 514, no. 7521, pp. 187–192, 2014.
View at: Publisher Site | Google Scholar
D. Yang, Y. He, R. Munoz-Planillo, Q. Liu, and G. Nunez, “Caspase-11 requires the pannexin-1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock,” Immunity, vol. 43, no. 5, pp. 923–932, 2015.
View at: Publisher Site | Google Scholar
M. Deng, Y. Tang, W. Li et al., “The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis,” Immunity, vol. 49, no. 4, pp. 740–753, 2018.
View at: Publisher Site | Google Scholar
J. A. Hagar, D. A. Powell, Y. Aachoui, R. K. Ernst, and E. A. Miao, “Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock,” Science, vol. 341, no. 6151, pp. 1250–1253, 2013.
View at: Publisher Site | Google Scholar
Y. Tang, X. Wang, Z. Li et al., “Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties,” Immunity, vol. 54, no. 3, pp. 454–467 e6, 2021.
View at: Publisher Site | Google Scholar
X. Chen, W. T. He, L. Hu et al., “Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis,” Cell Research, vol. 26, no. 9, pp. 1007–1020, 2016.
View at: Publisher Site | Google Scholar
Z. Zhaolin, L. Guohua, W. Shiyuan, and W. Zuo, “Role of pyroptosis in cardiovascular disease,” Cell Proliferation, vol. 52, no. 2, Article ID e12563, 2019.
View at: Publisher Site | Google Scholar
S. B. Kovacs and E. A. Miao, “Gasdermins: effectors of pyroptosis,” Trends in Cell Biology, vol. 27, no. 9, pp. 673–684, 2017.
View at: Publisher Site | Google Scholar
M. M. Gaidt and V. Hornung, “Alternative inflammasome activation enables IL-1β release from living cells,” Current Opinion in Immunology, vol. 44, pp. 7–13, 2017.
View at: Publisher Site | Google Scholar
C. Semino, S. Carta, M. Gattorno, R. Sitia, and A. Rubartelli, “Progressive waves of IL-1β release by primary human monocytes via sequential activation of vesicular and gasdermin D-mediated secretory pathways,” Cell Death & Disease, vol. 9, no. 11, p. 1088, 2018.
View at: Publisher Site | Google Scholar
C. L. Evavold, J. Ruan, Y. Tan, S. Xia, H. Wu, and J. C. Kagan, “The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages,” Immunity, vol. 48, no. 1, pp. 35–44 e6, 2018.
View at: Publisher Site | Google Scholar
P. Broz, P. Pelegrin, and F. Shao, “The gasdermins, a protein family executing cell death and inflammation,” Nature Reviews Immunology, vol. 20, no. 3, pp. 143–157, 2020.
View at: Publisher Site | Google Scholar
M. Monteleone, A. C. Stanley, K. W. Chen et al., “Interleukin-1β maturation triggers its relocation to the plasma membrane for gasdermin-D-dependent and -independent secretion,” Cell Reports, vol. 24, no. 6, pp. 1425–1433, 2018.
View at: Publisher Site | Google Scholar
R. Heilig, M. S. Dick, L. Sborgi, E. Meunier, S. Hiller, and P. Broz, “The gasdermin-D pore acts as a conduit for IL-1β secretion in mice,” European Journal of Immunology, vol. 48, no. 4, pp. 584–592, 2018.
View at: Publisher Site | Google Scholar
W. T. He, H. Wan, L. Hu et al., “Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion,” Cell Research, vol. 25, no. 12, pp. 1285–1298, 2015.
View at: Publisher Site | Google Scholar
M. Takahashi, “Cell-specific roles of NLRP3 inflammasome in myocardial infarction,” Journal of Cardiovascular Pharmacology, vol. 74, no. 3, pp. 188–193, 2019.
View at: Publisher Site | Google Scholar
W. Sun, S. Dong, H. Lu et al., “Beclin-1 overexpression regulates NLRP3 activation by promoting TNFAIP3 in microvascular injury following myocardial reperfusion,” Cellular Signalling, vol. 84, Article ID 110008, 2021.
View at: Publisher Site | Google Scholar
Z. Yan, Z. Qi, X. Yang et al., “The NLRP3 inflammasome: multiple activation pathways and its role in primary cells during ventricular remodeling,” Journal of Cellular Physiology, vol. 236, no. 8, pp. 5547–5563, 2021.
View at: Publisher Site | Google Scholar
Y. Liu, P. Li, C. Qiao et al., “Chitosan hydrogel enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction by alleviating vascular endothelial cell pyroptosis,” Journal of Cardiovascular Pharmacology, vol. 75, no. 1, pp. 75–83, 2020.
View at: Publisher Site | Google Scholar
X. Jiang, B. R. Stockwell, and M. Conrad, “Ferroptosis: mechanisms, biology and role in disease,” Nature Reviews Molecular Cell Biology, vol. 22, no. 4, pp. 266–282, 2021.
View at: Publisher Site | Google Scholar
A. Seiler, M. Schneider, H. Forster et al., “Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death,” Cell Metabolism, vol. 8, no. 3, pp. 237–248, 2008.
View at: Publisher Site | Google Scholar
M. Conrad and D. A. Pratt, “The chemical basis of ferroptosis,” Nature Chemical Biology, vol. 15, no. 12, pp. 1137–1147, 2019.
View at: Publisher Site | Google Scholar
V. E. Kagan, G. Mao, F. Qu et al., “Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis,” Nature Chemical Biology, vol. 13, no. 1, pp. 81–90, 2017.
View at: Publisher Site | Google Scholar
J. H. Kim, T. M. Lewin, and R. A. Coleman, “Expression and characterization of recombinant rat acyl-CoA synthetases 1, 4, and 5,” Journal of Biological Chemistry, vol. 276, no. 27, pp. 24667–24673, 2001.
View at: Publisher Site | Google Scholar
S. Doll, B. Proneth, Y. Y. Tyurina et al., “ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition,” Nature Chemical Biology, vol. 13, no. 1, pp. 91–98, 2017.
View at: Publisher Site | Google Scholar
Y. Tian, J. Lu, X. Hao et al., “FTH1 inhibits ferroptosis through ferritinophagy in the 6-OHDA model of Parkinson’s disease,” Neurotherapeutics, vol. 17, no. 4, pp. 1796–1812, 2020.
View at: Publisher Site | Google Scholar
Y. Fang, X. Chen, Q. Tan, H. Zhou, J. Xu, and Q. Gu, “Inhibiting ferroptosis through disrupting the NCOA4–FTH1 interaction: a new mechanism of action,” ACS Central Science, vol. 7, no. 6, pp. 980–989, 2021.
View at: Publisher Site | Google Scholar
X. Wu, Y. Li, S. Zhang, and X. Zhou, “Ferroptosis as a novel therapeutic target for cardiovascular disease,” Theranostics, vol. 11, no. 7, pp. 3052–3059, 2021.
View at: Publisher Site | Google Scholar
X. Chen, R. Kang, G. Kroemer, and D. Tang, “Broadening horizons: the role of ferroptosis in cancer,” Nature Reviews Clinical Oncology, vol. 18, no. 5, pp. 280–296, 2021.
View at: Publisher Site | Google Scholar
A. Ajoolabady, H. Aslkhodapasandhokmabad, P. Libby et al., “Ferritinophagy and ferroptosis in the management of metabolic diseases,” Trends in Endocrinology and Metabolism, vol. 32, no. 7, pp. 444–462, 2021.
View at: Publisher Site | Google Scholar
W. D. Bao, P. Pang, X. T. Zhou et al., “Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease,” Cell Death & Differentiation, vol. 28, no. 5, pp. 1548–1562, 2021.
View at: Publisher Site | Google Scholar
X. Chen, R. Kang, G. Kroemer, and D. Tang, “Ferroptosis in infection, inflammation, and immunity,” Journal of Experimental Medicine, vol. 218, no. 6, 2021.
View at: Google Scholar
T. J. Park, J. H. Park, G. S. Lee et al., “Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes,” Cell Death & Disease, vol. 10, no. 11, p. 835, 2019.
View at: Publisher Site | Google Scholar
C. Yifan, S. Jianfeng, and P. Jun, “Development and validation of a random forest diagnostic model of acute myocardial infarction based on ferroptosis-related genes in circulating endothelial cells,” Frontiers in Cardiovascular Medicine, vol. 8, Article ID 663509, 2021.
View at: Publisher Site | Google Scholar
N. Mizushima and B. Levine, “Autophagy in human diseases,” New England Journal of Medicine, vol. 383, no. 16, pp. 1564–1576, 2020.
View at: Publisher Site | Google Scholar
B. Levine and G. Kroemer, “Biological functions of autophagy genes: a disease perspective,” Cell, vol. 176, pp. 11–42, 2019.
View at: Publisher Site | Google Scholar
D. Gatica, V. Lahiri, and D. J. Klionsky, “Cargo recognition and degradation by selective autophagy,” Nature Cell Biology, vol. 20, no. 3, pp. 233–242, 2018.
View at: Publisher Site | Google Scholar
D. J. Klionsky, P. Codogno, A. M. Cuervo et al., “A comprehensive glossary of autophagy-related molecules and processes,” Autophagy, vol. 6, no. 4, pp. 438–448, 2010.
View at: Publisher Site | Google Scholar
I. Dikic and Z. Elazar, “Mechanism and medical implications of mammalian autophagy,” Nature Reviews Molecular Cell Biology, vol. 19, no. 6, pp. 349–364, 2018.
View at: Publisher Site | Google Scholar
K. R. Parzych and D. J. Klionsky, “An overview of autophagy: morphology, mechanism, and regulation,” Antioxidants and Redox Signaling, vol. 20, no. 3, pp. 460–473, 2014.
View at: Publisher Site | Google Scholar
J. Zou, Q. Fei, H. Xiao et al., “VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy,” Journal of Cellular Physiology, vol. 234, no. 10, pp. 17690–17703, 2019.
View at: Publisher Site | Google Scholar
F. Xie, S. Xu, Y. Lu et al., “Metformin accelerates zebrafish heart regeneration by inducing autophagy,” NPJ Regenerative Medicine, vol. 6, no. 1, p. 62, 2021.
View at: Publisher Site | Google Scholar
Q. Lu, Y. Yao, Z. Hu et al., “Angiogenic factor AGGF1 activates autophagy with an essential role in therapeutic angiogenesis for heart disease,” PLoS Biology, vol. 14, no. 8, Article ID e1002529, 2016.
View at: Publisher Site | Google Scholar
H. Liu, S. Liu, X. Qiu et al., “Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells,” Autophagy, vol. 16, no. 12, pp. 2140–2155, 2020.
View at: Publisher Site | Google Scholar
Q. Su, X. W. Lv, Y. L. Xu et al., “Exosomal LINC00174 derived from vascular endothelial cells attenuates myocardial I/R injury via p53-mediated autophagy and apoptosis,” Molecular Therapy—Nucleic Acids, vol. 23, pp. 1304–1322, 2021.
View at: Publisher Site | Google Scholar
Y. Zi, Y. Yi-An, J. Bing et al., “Sirt6-induced autophagy restricted TREM-1-mediated pyroptosis in ox-LDL-treated endothelial cells: relevance to prognostication of patients with acute myocardial infarction,” Cell Death & Disease, vol. 5, no. 1, p. 88, 2019.
View at: Publisher Site | Google Scholar
E. E. Varfolomeev, M. Schuchmann, V. Luria et al., “Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, fas/apo1, and DR3 and is lethal prenatally,” Immunity, vol. 9, no. 2, pp. 267–276, 1998.
View at: Publisher Site | Google Scholar
K. Newton, A. W. Harris, M. L. Bath, K. G. Smith, and A. Strasser, “A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes,” The EMBO Journal, vol. 17, no. 3, pp. 706–718, 1998.
View at: Publisher Site | Google Scholar
W. J. Kaiser, J. W. Upton, A. B. Long et al., “RIP3 mediates the embryonic lethality of caspase-8-deficient mice,” Nature, vol. 471, no. 7338, pp. 368–372, 2011.
View at: Publisher Site | Google Scholar
A. Oberst, C. P. Dillon, R. Weinlich et al., “Catalytic activity of the caspase-8-FLIP (L) complex inhibits RIPK3-dependent necrosis,” Nature, vol. 471, no. 7338, pp. 363–367, 2011.
View at: Publisher Site | Google Scholar
K. Newton, K. E. Wickliffe, A. Maltzman et al., “Activity of caspase-8 determines plasticity between cell death pathways,” Nature, vol. 575, no. 7784, pp. 679–682, 2019.
View at: Publisher Site | Google Scholar
J. E. Vince, D. De Nardo, W. Gao et al., “The mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1β activation,” Cell Reports, vol. 25, no. 9, pp. 2339–2353, 2018.
View at: Publisher Site | Google Scholar
C. Y. Taabazuing, M. C. Okondo, and D. A. Bachovchin, “Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages,” Cell Chemical Biology, vol. 24, no. 4, pp. 507–514, 2017.
View at: Publisher Site | Google Scholar
S. M. Man, P. Tourlomousis, L. Hopkins, T. P. Monie, K. A. Fitzgerald, and C. E. Bryant, “Salmonella infection induces recruitment of caspase-8 to the inflammasome to modulate IL-1β production,” The Journal of Immunology, vol. 191, no. 10, pp. 5239–5246, 2013.
View at: Publisher Site | Google Scholar
D. P. A. Mascarenhas, D. M. Cerqueira, M. S. F. Pereira et al., “Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the naip5/NLRC4/ASC inflammasome,” PLoS Pathogens, vol. 13, no. 8, Article ID e1006502, 2017.
View at: Publisher Site | Google Scholar
M. Doerflinger, Y. Deng, P. Whitney et al., “Flexible usage and interconnectivity of diverse cell death pathways protect against intracellular infection,” Immunity, vol. 53, no. 3, pp. 533–547 e7, 2020.
View at: Publisher Site | Google Scholar
R. Heilig, M. Dilucca, D. Boucher et al., “Caspase-1 cleaves bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD,” Life Sci Alliance, vol. 3, no. 6, 2020.
View at: Google Scholar
D. Frank and J. E. Vince, “Pyroptosis versus necroptosis: similarities, differences, and crosstalk,” Cell Death & Differentiation, vol. 26, no. 1, pp. 99–114, 2019.
View at: Publisher Site | Google Scholar
B. Zhou, J. Liu, R. Kang, D. J. Klionsky, G. Kroemer, and D. Tang, “Ferroptosis is a type of autophagy-dependent cell death,” Seminars in Cancer Biology, vol. 66, pp. 89–100, 2020.
View at: Publisher Site | Google Scholar
W. Hou, Y. Xie, X. Song et al., “Autophagy promotes ferroptosis by degradation of ferritin,” Autophagy, vol. 12, no. 8, pp. 1425–1428, 2016.
View at: Publisher Site | Google Scholar
E. Desideri, G. Filomeni, and M. R. Ciriolo, “Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells,” Autophagy, vol. 8, no. 12, pp. 1769–1781, 2012.
View at: Publisher Site | Google Scholar
Y. Sun, Y. Zheng, C. Wang, and Y. Liu, “Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells,” Cell Death & Disease, vol. 9, no. 7, p. 753, 2018.
View at: Publisher Site | Google Scholar
S. Bedoui, M. J. Herold, and A. Strasser, “Emerging connectivity of programmed cell death pathways and its physiological implications,” Nature Reviews Molecular Cell Biology, vol. 21, no. 11, pp. 678–695, 2020.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Mingyue Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

865

Downloads

922

Citations