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(Circulation Research. 1999;85:e44.)
© 1999 American Heart Association, Inc.

UltraRapid Communications

Permanent Cardiovascular Protection From Hypertension by the AT₁ Receptor Antisense Gene Therapy in Hypertensive Rat Offspring

Phyllis Y. Reaves¹, Craig H. Gelband¹, Hongwei Wang¹, Hong Yang, Di Lu, Kathleen H. Berecek, Michael J. Katovich, Mohan K. Raizada

From the Department of Physiology (P.Y.R., C.H.G., H.W., H.Y., D.L., M.K.R.), College of Medicine, Department of Pharmacodynamics (M.J.K.), College of Pharmacy, University of Florida, Gainesville, Fla; Department of Physiology and Biophysics (K.H.B.), University of Alabama, Birmingham, Ala.

Correspondence to Mohan K. Raizada, PhD, Professor, Department of Physiology, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610. E-mail mraizada{at}phys.med.ufl.edu

Abstract—Our previous studies have demonstrated that the introduction of angiotensin II type I receptor antisense (AT₁R-AS) cDNA by a retrovirally mediated delivery system prevents the development of hypertension in the spontaneously hypertensive rat (SHR), an animal model for primary hypertension in humans. These results have led us to propose the hypothesis that an interruption of the renin-angiotensin system (RAS) activity at a genetic level would prevent hypertension on a permanent basis. F₁ and F₂ generations of offspring from a retroviral vector, LNSV- and LNSV-AT₁R-AS–treated SHR, were generated, and various physiological parameters indicative of hypertension were studied and compared with those of their parents to investigate this hypothesis. Both F₁ and F₂ generations of LNSV-AT₁R-AS–treated SHR expressed a persistently lower blood pressure, decreased cardiac hypertrophy and fibrosis, decreased medial thickness, and normalization of renal artery excitation-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 observed in the LNSV-AT₁R-AS–treated SHR parent. The prevention of cardiovascular pathophysiology and expression of normotensive phenotypes are, at least in part, a result of integration and subsequent transmission of AT₁R-AS from the SHR parents to offspring. These data demonstrate that a single intracardiac injection of LNSV-AT₁R-AS causes a permanent cardiovascular protection against hypertension as a result of a genomic integration and germ line transmission of the AT₁R-AS in the SHR offspring. The full text of this article is available at http://www.circresaha.org.

Key Words: AT₁ receptor antisense • gene therapy • hypertension • SHR • antisense transmission to offspring