Permanent cardiovascular protection from hypertension by the AT(1) receptor antisense gene therapy in hypertensive rat offspring

Our previous studies have demonstrated that the introduction of angiotensin II type I receptor antisense (AT(1)R-AS) cDNA by a retrovirally mediated d elivery system prevents the development of hypertension in the spontaneousl y hypertensive rat (SHR), an animal model for primary hypertension in human s. These results have led us to propose the hypothesis that an interruption of the renin-angiotensin system (RAS) activity at a genetic level would pr event hypertension on a permanent basis. F-1 and F-2 generations of offspri ng from a retroviral vector, LNSV- and LNSV-AT(1)R-AS-treated SHR, were gen erated, and various physiological parameters indicative of hypertension wer e studied and compared with those of their parents to investigate this hypo thesis. Both F-1 and F-2 generations of LNSV-AT(1)R-AS-treated SHR expresse d a persistently lower blood pressure, decreased cardiac hypertrophy and fi brosis, decreased medial thickness, and normalization of renal artery excit ation-contraction coupling, Ca2+ current, and [Ca2+](i) when compared with offspring derived from the LNSV-treated SHR. In fact, the magnitude of the prevention of these pathophysiological alterations was similar to that obse rved in the LNSV-AT(1)R-AS-treated SHR parent. The prevention of cardiovasc ular pathophysiology and expression of normotensive phenotypes are, at leas t in part, a result of integration and subsequent transmission of AT(1)R-AS from the SHR parents to offspring. These data demonstrate that a single in tracardiac injection of LNSV-AT(1)R-AS causes a permanent cardiovascular pr otection against hypertension as a result of a genomic integration and germ line transmission of the AT(1)R-AS in the SHR offspring. The full text of this article is available at http://www.circresaha.org.