Angiotensin II (Ang II), acting through its G protein-coupled AT1 receptor (AT1), contributes to the precocious heart senescence typical of patients with hypertension, atherosclerosis, and diabetes. AT1 was suggested to transactivate an intracellular signaling controlled by growth factors and their tyrosin-kinase receptors. In cultured vascular smooth muscle cells, this downstream mechanism comprises the p66Shc adaptor protein, previously recognized to play a role in vascular cell senescence and death. The aim of the present study was 2-fold: (1) to characterize the cardiovascular phenotype of p66Shc knockout mice (p66Shc(-/-)), and (2) to test the novel hypothesis that disrupting the p66Shc might protect the heart from the damaging action of elevated Ang II levels. Compared with wild-type littermates (p66Shc(+/+)), p66Shc(-/-) showed similar blood pressure, heart rate, and left ventricular wall thickness. However, cardiomyocyte number was increased in mutant animals, indicating a condition of myocardial hyperplasia. In p66Shc(+/+), infusion of a sub-pressor dose of Ang II (300 nmol/kg body weight [BW] daily for 28 days) caused left ventricular hypertrophy and apoptotic death of cardiomyocytes and endothelial cells. In contrast, p66Shc(-/-) were resistant to the proapoptotic/hypertrophic action of Ang II. Consistently, in vitro experiments showed that Ang II causes apoptotic death of cardiomyocytes isolated from p66Shc(+/+) hearts to a greater extent as compared with p66Shc(-/-) cardiomyocytes. Our results indicate a fundamental role of p66Shc in Ang II-mediated myocardial remodeling. In perspective, p66Shc inhibition may be envisioned as a novel way to prevent the deleterious effects of Ang II on the heart.
Genetic deletion of the p66Shc adaptor protein protects from angiotensin II-induced myocardial damage / G. Graiani; C. Lagrasta; E. Migliaccio; F. Spillmann; M. Meloni; P. Madeddu; F. Quaini; IM. Padura; L. Lanfrancone; P.Pelicci; C. Emanueli. - In: HYPERTENSION. - ISSN 0194-911X. - 46(2005), pp. 433-440. [10.1161/01.HYP.0000174986.73346.ba]
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