Genetic deletion of the p66^Shc adaptor protein protects from angiotensin II–induced myocardial damage

Graiani, G. et al. (2005) Genetic deletion of the p66^Shc adaptor protein protects from angiotensin II–induced myocardial damage. Hypertension, 46(2), pp. 433-440. (doi: 10.1161/01.HYP.0000174986.73346.ba)

Abstract

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 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 <i>p66^Shc</i> knockout mice (<i>p66^Shc−/−</i>), and (2) to test the novel hypothesis that disrupting the <i>p66^Shc</i> might protect the heart from the damaging action of elevated Ang II levels. Compared with wild-type littermates (<i>p66^Shc+/+</i>), <i>p66^Shc−/−</i> 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 <i>p66^Shc+/+</i>, 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, <i>p66^Shc−/−</i> 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 <i>p66^Shc+/+</i> hearts to a greater extent as compared with <i>p66^Shc−/−</i> 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Meloni, Dr Marco
• Authors: Graiani, G., Lagrasta, C., Migliaccio, E., Spillmann, F., Meloni, M., Madeddu, P., Quaini, F., Padura, I. M., Lanfrancone, L., Pelicci, P., and Emanueli, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Hypertension
• Publisher: American Heart Association
• ISSN: 0194-911X
• ISSN (Online): 1524-4563