Abstract 14788: Angiotensin II Type 1 Receptor-Associated Protein Mediates a Novel Inhibitory Effect on Cardiac Hypertrophy In Vivo
We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor-associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II-mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy in vivo. We first examined the effect of angiotensin II infusion (200 ng/kg per minute) for 2 weeks on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy (HW/BW, 4.05 vs 4.58 mg/g, P<0.05), concomitant with a significant decrease in cardiac ATRAP expression (relative LV ATRAP mRNA level, 100 vs 25%, P<0.05), but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the alpha-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy (HW/BW, vehicle vs Ang II, 4.15 vs 4.79 mg/g in wild-type mice, P<0.05; 4.19 vs 4.24 mg/g in cardiac ATRAP transgenic mice, not significant), activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice (SBP, 129 vs 145 mm Hg in the dark period in wild-type mice, P<0.05; 129 vs 143 mm Hg in the dark period in cardiac ATRAP transgenic mice, P<0.05). These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy.
- © 2010 by American Heart Association, Inc.