Renin-angiotensin system (RAS) plays an important role in the control of blood pressure (BP) and its altered expression is of a major pathophysiological consequence in hypertension, stroke and other cardiovascular-related diseased states. The understanding of the cellular, molecular and physiological mechanisms involved in altered expression of RAS in hypertension has resulted in the development of many successful pharmacological approaches for the management and control of hypertension. In spite of this pharmacological intervention of hypertension, it suffers from a lingering drawback of """"""""compliance"""""""" since the drugs have to be administered on a daily basis. Recent advances in gene targeting and gene therapy, coupled with our understanding of the regulation of genes of RAS, has led us to investigate the possibility of a genetic intervention of RAS in the control and prevention of this pathophysiological condition. This proposal takes advantage of a diverse expertise of the research group and impressive preliminary data in an attempt to support/refute the hypothesis that the delivery of Ang II type 1 receptor (AT1R) antisense cDNA into Ang II target tissues would decrease AT1R expression and thus, would result in a long-term attenuation of high BP and other pathophysiological conditions associated with the hypertensive state. The investigators propose to utilize viral vectors to deliver AT1R-AS into cells in vitro and in vivo.
The aims of their study are: (I) characterize viral-mediated delivery of AT1R-AS in neuronal and vascular smooth muscle cells, (ii) investigate the cellular and physiological consequences of AT1R-AS gene delivery in spontaneously hypertensive (SH) rats, (iii) determine if intervention of the AT1R system by AT1R-AS would irreversibly interrupt the development of hypertension in SH rats, and (iv) validate the usefulness of antihypertensive actions of AT1R-AS gene delivery in other models (renovascular, renin transgenic and fructose-fed insulin resistant) of hypertension. Thus, they believe that their research proposal is of relatively low risk in nature but will have a high impact in developing strategies for a long-term treatment and possibly prevention of Ang II-dependent hypertension in animals. If successful, the approach has the potential to be immediately adapted for the long-term treatment of this disease in humans.
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