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(Circulation. 2002;105:402.)
© 2002 American Heart Association, Inc.

Editorials

Apoptosis Signal-Regulating Kinase/Nuclear Factor-B

A Novel Signaling Pathway Regulates Cardiomyocyte Hypertrophy

Thomas Force, MD; Syed Haq, MD; Heiko Kilter, MD; Ashour Michael, PhD

From the Molecular Cardiology Research Institute, New England Medical Center and the Department of Medicine, Tufts University School of Medicine, Boston, Mass.

Correspondence to Thomas Force, MD, Molecular Cardiology Research Institute, New England Medical Center, 750 Washington St, Box 8486, Boston, MA 02111. E-mail tforce@lifespan.org

Key Words: Editorials • angiotensin • heart failure • signal transduction • oxidant stress

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 -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 . . . [Full Text of this Article]

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