Genetic Deletion of the p66 Shc Adaptor Protein Protects From Angiotensin II–Induced Myocardial Damage

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Abstract
Angiotensin II (Ang II), acting through its G protein–coupled AT 1 receptor (AT 1 ), contributes to the precocious heart senescence typical of patients with hypertension, atherosclerosis, and diabetes. AT 1 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 p66 Shc 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 p66 Shc knockout mice ( p66 Shc −/− ), and (2) to test the novel hypothesis that disrupting the p66 Shc might protect the heart from the damaging action of elevated Ang II levels. Compared with wild-type littermates ( p66 Shc +/+ ), p66 Shc −/− 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 p66 Shc +/+ , 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, p66 Shc −/− 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 p66 Shc +/+ hearts to a greater extent as compared with p66 Shc −/− cardiomyocytes. Our results indicate a fundamental role of p66 Shc in Ang II–mediated myocardial remodeling. In perspective, p66 Shc inhibition may be envisioned as a novel way to prevent the deleterious effects of Ang II on the heart.