The Mitochondrial Death Pathway and Cardiac Myocyte Apoptosis

Abstract

Abstract-Apoptosis has been causally linked to the pathogenesis of myocardial infarction and heart failure in rodent models. This death process is mediated by two central pathways, an extrinsic pathway involving cell surface receptors and an intrinsic pathway using mitochondria and the endoplasmic reticulum. Each of these pathways has been implicated in myocardial pathology. In this review, we summarize recent advances in the understanding of the intrinsic pathway and how it relates to cardiac myocyte death and heart disease. Key Words: apoptosis Ⅲ necrosis Ⅲ cell death Ⅲ mitochondria Ⅲ Bcl-2 Ⅲ caspase Ⅲ death-inducing signaling complex Ⅲ apoptosome Ⅲ ischemia Ⅲ heart failure O ver the past decade, interest in cell death has intensified among scientists in multiple areas of biology and medicine. This fascination has been driven by the discovery that apoptosis is mediated by an ancient program that is hard-wired into all metazoan cells. Renewed attention in the cardiovascular field has been fueled by the notion that cell death is often an active process that, in principle, can be inhibited in various disease states.

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

“…hernia), followed by cytC release. 4,10 The present study showed that the use of Na-free medium largely prevented H 2 O 2 -induced mitochondrial hernia formation and loss of cristae (arrow heads, Figure 5Hc), but did not protect the plasma membrane (arrows), suggesting that the (Figures 2a, 5A and C) was important in OMM disruption and clotrimazolesensitive cytC release ( Figure 5D). Cotreatment with 3-AB (PARP inhibition) and clotrimazole (inhibition of both Na þ / Ca 2 þ influx) markedly prevented the mitochondrial swelling, OMM disruption (arrow heads), plasma membrane permeabilization (arrows in Figure 5Hb), and chromatin fragmentation normally seen after 4.5 h exposure to H 2 O 2 (inset, Figures 2fii and 5Hb), again showing that activation of both TRPM2 and PARP was involved in the generation of the mixed features of cell death ( Figure 6).…”

“…1,2 Different types of myocyte death during I/R injury have been demonstrated, including apoptosis [2][3][4] and necrosis. 5,6 The hallmarks of apoptosis are usually an intact membrane, chromatin condensation, and nuclear fragmentation.…”

“…7 The key events in the mitochondrial-dependent apoptotic pathway are the opening of the cyclosporin A (CsA)-sensitive permeability transition pore (PTP), resulting in the release of cytochrome c (cytC) and other apoptogenic proteins, and in caspase 3-dependent nuclear condensation/fragmentation. 4,[8][9][10] ROSinduced mitochondrial Ca 2 þ ([Ca 2 þ ] m ) overload is one of the major causes of PTP opening and cytC release, resulting in myocyte apoptosis. 4,11 In contrast, necrosis is commonly characterized by an increase in plasma membrane permeability, release of intracellular proteins, and an absence of nuclear morphological changes.…”

“…4,[8][9][10] ROSinduced mitochondrial Ca 2 þ ([Ca 2 þ ] m ) overload is one of the major causes of PTP opening and cytC release, resulting in myocyte apoptosis. 4,11 In contrast, necrosis is commonly characterized by an increase in plasma membrane permeability, release of intracellular proteins, and an absence of nuclear morphological changes. 7,12 One major hypothesis for I/R-induced necrotic cell death is that ROS-induced DNA damage results in excessive activation of the nuclear repair enzymes, the poly(ADP-ribose) polymerases (PARPs).…”

Exercise training enhanced SIRT1 longevity signaling replaces the IGF1 survival pathway to attenuate aging-induced rat heart apoptosis

“…In mammalian cells, there are two major apoptotic pathways divided into intrinsic mitochondrial and extrinsic death receptor activation (Crow et al 2004;Fischer et al 2004). Extrinsic death receptor activation is a predisposing factor for inducing apoptosis in other immune system cells.…”