The major cardiac syndromes, myocardial infarction and heart failure, are responsible for a large portion of deaths worldwide. Genetic and pharmacological manipulations indicate that cell death is an important component in the pathogenesis of both diseases. Cells die primarily by apoptosis or necrosis, and autophagy has been associated with cell death. Apoptosis has long been recognized as a highly regulated process. Recent data indicate that a significant subset of necrotic deaths is also highly programmed. In this review, we discuss the molecular mechanisms that underlie these forms of cell death and their interconnections. Because of their regulated nature, the possibility is raised that small molecules aimed at inhibiting cell death may provide novel therapies for these common and lethal heart syndromes.

The defining event in apoptosis is mitochondrial outer membrane permeabilization (MOMP), allowing apoptogen release. In contrast, the triggering event in primary necrosis is early opening of the inner membrane mitochondrial permeability transition pore (mPTP), precipitating mitochondrial dysfunction and cessation of ATP synthesis. Bcl-2 proteins Bax and Bak are the principal activators of MOMP and apoptosis. Unexpectedly, we find that deletion of Bax and Bak dramatically reduces necrotic injury during myocardial infarction in vivo. Triple knockout mice lacking Bax/Bak and cyclophilin D, a key regulator of necrosis, fail to show further reduction in infarct size over those deficient in Bax/Bak. Absence of Bax/Bak renders cells resistant to mPTP opening and necrosis, effects confirmed in isolated mitochondria. Reconstitution of these cells or mitochondria with wild-type Bax, or an oligomerization-deficient mutant that cannot support MOMP and apoptosis, restores mPTP opening and necrosis, implicating distinct mechanisms for Bax-regulated necrosis and apoptosis. Both forms of Bax restore mitochondrial fusion in Bax/Bak-null cells, which otherwise exhibit fragmented mitochondria. Cells lacking mitofusin 2 (Mfn2), which exhibit similar fusion defects, are protected to the same extent as Bax/Bak-null cells. Conversely, restoration of fused mitochondria through inhibition of fission potentiates mPTP opening in the absence of Bax/Bak or Mfn2, indicating that the fused state itself is critical. These data demonstrate that Bax-driven fusion lowers the threshold for mPTP opening and necrosis. Thus, Bax and Bak play wider roles in cell death than previously appreciated and may be optimal therapeutic targets for diseases that involve both forms of cell death.

Abstract:It is well known that apoptosis is an actively mediated cell suicide process. In contrast, necrosis, a morphologically distinct form of cell death, has traditionally been regarded as passive and unregulated. Over the past decade, however, experiments in Caenorhabditis elegans and mammalian cells have revealed that a significant proportion of necrotic death is, in fact, actively mediated by the doomed cell. Although a comprehensive understanding of necrosis is still lacking, some key molecular events have come into focus. Cardiac myocyte apoptosis and necrosis are prominent features of the major cardiac syndromes. Accordingly, the recognition of necrosis as a regulated process mandates a reexamination of cell death in the heart. This review discusses pathways that mediate programmed necrosis, how they intersect with apoptotic pathways, roles of necrosis in heart disease, and new therapeutic opportunities that the regulated nature of necrosis presents. (Circ Res. 2011;108:1017-1036.) Key Words: cell death Ⅲ necrosis Ⅲ apoptosis Ⅲ myocardial infarction Ⅲ heart failure A s recently as 30 years ago, cell death was viewed as a passive and unregulated process. Irreversible cellular injury (from physical/chemical/biological insults) was thought to kill solely by overwhelming cellular homeostasis. In this model, the cell was merely the recipient of damage and not a participant in its own demise. Unexplained by this paradigm, however, were the highly reproducible deaths of specific cells during the development of multiple organisms. In fact, these developmental cell deaths (termed "programmed cell death") had long been recognized but remained poorly understood. Studies in Caenorhabditis elegans showed that a relatively small network of genes (ced-9-|ced-43ced-3) regulates the deletion of a specific 131 cells during development. 1,2 These experiments provided the first evidence that any form of cell death was actively mediated. Subsequent work demonstrated that these genes had been conserved for more than 600 million years of evolution to humans. The orthologs of ced-9, ced-4, and ced-3 are, respectively, the bcl-2 (B-cell lymphoma 2) family, apaf-1 (apoptotic protease activating factor-1), and the caspase family. 3 Moreover, not only do these genes regulate developmental cell deaths in mammals, they also control the deaths of postnatal cells by a specific process termed apoptosis (discussed below). Taken together, these observations establish that cells often die through active mechanisms that have been highly conserved through evolution.Research more than the past 2 decades has built on these observations to produce a relatively mature understanding of the pathways that mediate apoptosis. These include an intrinsic pathway, which is conserved back to C elegans, that uses mitochondria and endoplasmic reticulum; and an extrinsic pathway that involves cell surface death receptors. These pathways are critical in the regulation of apoptosis. 3 Apoptosis is characterized by cell shrinkage and fragmentation into membra...

CaMKII (the multifunctional Ca2+ and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.