Defining the role of the angiotensin II type 2 receptor in cardiovascular disease.

摘要

Despite recent advances in understanding the renin angiotensin system, the role of the angiotensin II type 2 receptor (AT2R) in cardiovascular diseases remains elusive. Given that the AT2R has been implicated to play a role in embryonic development, traditional transgenic animal models may not be an effective means for studying the role of the AT2R. To overcome the inherent problems of compensatory gene expression with transgenic animals, we developed a lentiviral vector system in which overexpression of the AT2R could be accomplished after embryonic development. By injecting lentiviral vector either directly into the heart or into specific brain regions, we were able to study both the peripheral and the central actions of this receptor. In addition, this same vector was used to characterize the AT2R in vitro in cells that are typically difficult to transduce.; These studies indicate that the AT2R plays a cardioprotective role in several models of disease. Overexpression of the AT2R in the heart prevents the development of cardiac hypertrophy and heart failure in both a genetic model of hypertension and one with AngII-induction. In addition, the AT2R prevents migration in human coronary artery endothelial cells. This effect could prevent angiogenesis and its induction of atherosclerosis. Additionally, microarray analysis in these cells indicated a number of genes whose regulation may play a role in this effect. Finally, it appears that the AT2R in the paraventricular nucleus causes a decrease in water intake, both basally and in response to either dehydration or AngII. These effects could play a role to decrease circulatory volume, cardiac output, and blood pressure. All of which could prevent other cardiovascular abnormalities. These studies indicate that delivery of the AT2R by lentiviral vectors may provide a novel therapeutic option in the prevention of cardiovascular diseases.