In:
Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 2 ( 2005-08), p. 433-440
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.
Type of Medium:
Online Resource
ISSN:
0194-911X
,
1524-4563
DOI:
10.1161/01.HYP.0000174986.73346.ba
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2005
detail.hit.zdb_id:
2094210-2
