Abstract
Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation.
Highlights
Cell survival and death are fundamental for organ development, tissue homeostasis, and disease pathogenesis
Cell death was initially classified into three categories by Schweichel and Merker: type I that is associated with cell fragmentation and heterophagy, type II that is characterized by massive cytoplasmic vacuolization, and type III that is characterized by plasma membrane rupture and organelle swelling [1]
Based on earlier studies demonstrating that myocyterestricted deletion of focal adhesion kinase (FAK) exacerbated myocardial I/R injury [105], we demonstrated that cardiac-specific activation of FAK protected cardiomyocytes from I/R-induced apoptosis by enhancing NF-κB-dependent transcription of the prosurvival Bcl-2 family members Bcl-2 and Bcl-xl and X-linked inhibitor of apoptosis (XIAP, Figure 1) [106]
Summary
Cell survival and death are fundamental for organ development, tissue homeostasis, and disease pathogenesis. Ischemic preconditioning-induced, Akt-dependent phosphorylation and inactivation of its downstream target glycogen synthase kinase-3 (GSK-3) were initially speculated to confer cardioprotection because both preconditioning and pretreatment with GSK-3 inhibitors reduced infarct size to a similar extent [46] These findings were supported by transgenic studies showing that cardiac-specific expression of either GSK-3β or GSK-3α potentiated myocyte apoptosis, albeit through distinct mechanisms [47, 48]. FoxO1 may protect against apoptosis by forming a transcriptional complex with Yes-associated protein (YAP) and inducing expression of antioxidant genes catalase and manganese superoxide dismutase (MnSOD) [60, 61] Another FoxO family member, FoxO3a, has been shown to inhibit cardiomyocyte apoptosis and confers cardioprotection by inducing expression of apoptosis repressor with caspase recruitment domain (ARC), which attenuated oxidative stress-triggered sarcoplasmic reticulum Ca2+ release [62]. A most recent study showed that knockdown of FoxO1 that is exported from the nuclei following Apelin-13 stimulation exaggerated apoptosis, suggesting that cytosolic FoxO1 may directly inhibit apoptosis through a transcription activityindependent mechanism [63]
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