Apoptosis signal-regulating kinase/nuclear factor-κB: A novel signaling pathway regulates cardiomyocyte hypertrophy

Since 1993, when Sadoshima et al1 published their observations on the role of Angiotensin II (Ang II) in the stretch-induced hypertrophic response of cardiomyocytes, we have known that peptide hormones were important in the development of hypertrophy stimulated by cell stretch, the initiating stimulus in pressure overload-induced hypertrophy and in the hypertrophy that occurs in the noninfarcted myocardium following a myocardial infarction. Ang II, as well as endothelin-1 (ET-1) and α-adrenergic agents, activate intracellular pathways by binding to 7 transmembrane-spanning receptors coupled to heterotrimeric G proteins of the Gq class. The critical role of this class of receptors and G proteins in pressure overload-induced hypertrophy was elegantly demonstrated by Ahkter et al2 who showed that cardiac specific expression in mice of a peptide that blocked signal transmission by Gq markedly blunted the hypertrophic response to aortic banding. See p 509 The question that has dominated the field of cardiomyocyte biology is how do these hormones, acting via their cognate receptors and Gq, trigger the hypertrophic response? One clear conclusion has evolved thus far: the hypertrophic response of cardiomyocytes is regulated by an enormously complex network of interacting cytosolic signaling pathways.3 Gq activation ultimately results in the production of intermediates that increase cytosolic free [Ca2+] and activate members of the protein kinase C family, and leads to the recruitment of several protein kinases, including the mitogen-activated protein kinases (MAPKs), calcium calmodulin-dependent protein kinases, Akt/PKB, and the Janus kinases. These kinases phosphorylate a number of transcription factors, increasing their transcriptional activating activity and, in some cases, DNA binding activity. Elevated [Ca2+] can also activate the protein phosphatase, calcineurin,4 which dephosphorylates members of the nuclear factor-activated T cell (NF-AT) family of transcription factors, causing their nuclear translocation. Activated transcription factors bind to specific DNA sequences …