REGULATION OF AT1R ANTISENSE IN CONTROL OF HYPERTENSION

University Of Florida, Gainesville FL

Investigators

Abstract

Hypertension is a major risk factor for cardiovascular disease and has emerged as a tremendous economical and emotional burden on society. Thus, it is imperative that a permanent treatment and cure for this disease is discovered. We have developed a model that uses a retroviral-mediated gene delivery system to deliver antisense to the type 1 angiotensin receptor (AT1R-AS) to 5-day old rats. This delivery has profound beneficial effects on blood pressure and cardiac and renal pathophysiology in both the spontaneous hypertensive rat genetic model and in the chronic angiotensin II acquired hypertension model. Unfortunately, this system does not address critical issues of safety and efficacy. The ability to regulate expression of the therapeutic gene is crucial, because the therapeutic window or level of AS gene that is needed may vary during the course of the disease or between hypertensive individuals. Additionally, in cases of unanticipated side- effects it will be important to switch off expression of the AS gene. The purpose of this proposal then, is to develop a regulatable system for AT1R-AS wherein issues of safety and efficacy can be tested. We propose to infect two animal models of hypertension (genetic and acquired) with retroviral vectors harboring AT1R-AS under a tetracycline-regulatable promoter We will use these models to test the hypothesis that doxycycline, (Dox) a potent tetracycline derivative, can induce AT1R-AS expression and thus regulate its subsequent antihypertensive effects. Thus, specific aims of this research program will be as follows: 1. To characterize the efficiency and efficacy of RevTRE-AT1R-AS In vitro, 2. To determine the expression potential, physiological and cellular consequences of Dox-controlled AT1R-AS expression. 3. To test the efficacy of the Dox AT1R-AS system in chronic Ang II infusion model of hypertension.This project will have a profound impact on the way to treat and control hypertension and other cardiovascular diseases.