Prime Time for JNK-Mediated Akt Reactivation in Hypoxia-Reoxygenation

Abstract

See related article, pages 111–118 Despite continuous advances in cardiology, heart failure still remains one of the leading causes of morbidity and mortality in the world. Heart failure can be triggered by a variety of cellular changes within the myocardium leading to a loss of contractility, arrhythmias, and ventricular remodeling. For example, myocytes in a failing heart have been shown to exhibit changes in intracellular calcium handling and altered ion channels, as well as changes in metabolism and signal transduction.1 Given that myocytes have a limited ability for self-renewal, it follows that inappropriate cell death may also contribute to permanent ventricular remodeling and irretraceable heart failure.2,3 Not surprisingly, recent evidence has indicated that cardiomyocyte cell death by an apoptotic pathway may play a causal role in development of cardiomyopathies and heart disease more generally.4–6 Apoptosis is an energy-dependent cell suicide program that requires a change in gene expression. Two predominate pathways have been identified to be important for initiating the apoptotic program: a surface death receptor-mediated “extrinsic” pathway, and a mitochondria-mediated “intrinsic” pathway, both of which result in the activation of cellular proteases known as caspases.4,7 The former is activated by ligands such as TNF-α or Fas binding to cell surface death receptors, the latter activated by internal cues that follow cellular stresses including hypoxia, oxidative stress, toxins, and environmental triggers. An important family of proteins involved in regulating apoptosis is the Bcl-2 family, which includes both cytoprotective (Bcl-2, Bcl-XL) and apoptotic (Bid, Bax, Bad, Noxa, Puma, Bnip3) members. Collectively, these proteins regulate the intrinsic mitochondrial death pathway by influencing permeability of the outer and inner mitochondrial membranes6,8 The cell’s “decision” to live or die is derived from the dominance of either prodeath or prosurvival proteins and cellular factors. The accumulation of such …