Viral vector mediated gene therapy in multiple models of hypertension

Hypertension is a very complex and debilitating disease. Clinical and experimental studies have implicated a role of the hyperactive circulatory and tissue renin-angiotensin system (RAS) in the pathogenesis of hypertension. Effectiveness of pharmacological therapy has been limited due to associated side effects and patient compliance. In addition, these agents have multiple modes of action, thus making it difficult to decipher the exact mechanism of action.; Recent advances in molecular biology and gene delivery have led to the development of gene therapy as a novel therapeutic approach. Genetic polymorphism studies have identified the AT₁, receptor as a potential target for gene therapy. Previous studies from our lab have demonstrated long-term attenuation of blood pressure (BP) and cardiovascular pathophysiology by a single injection of a retroviral vector containing the AT₁, receptor antisense in the spontaneously hypertensive rat (SHR). However, specific mechanism by which AT₁R antisense blocks the development of hypertension in the SHR is difficult to elucidate because of the polygenic background of this animal model. Therefore, this dissertation investigated the efficacy of AT₁R antisense gene therapy in the renin transgenic rat (TGR), a monogenetic model of hypertension. In addition, previous studies had shown that antisense treatment or the pharmacological blockade of RAS does not affect BP in normotensive rats. Therefore, another hypothesis was to test if antisense treatment would not affect BP in normotensive rats but would block the subsequent development of Ang II dependent hypertension in these animals.; Untreated TGR rats exhibited fulminant hypertension and profound cardiac hypertrophy. Single antisense treatment resulted in mild reduction in BP in the TGR; however, the animals remained hypertensive. On the other hand hypertrophy was completely prevented in the antisense treated TGR. These results demonstrate for the first time that normalization of BP is not necessary to prevent hypertension-associated risk factors such as cardiac hypertrophy.; Results from the second study demonstrate that AT₁R antisense treatment has no effect on basal BP; however, antisense harboring rats are completely prevented from developing Ang II dependent hypertension. Collectively, these studies demonstrate that AT₁R antisense gene therapy may be an important tool not only to study the mechanisms behind RAS mediated hypertension, but also its use as a potential cure for the treatment of this disease.