doi: 10.1161/01.HYP.0000017827.63253.16
(Hypertension. 2002;39:969.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Blood Pressure–Independent Attenuation of Cardiac Hypertrophy by AT1R-AS Gene Therapy
From the Hypertension Center, Wake Forest University School of Medicine (C.M.F., D.M.D.), Winston-Salem, NC; Department of Pharmacodynamics, College of Pharmacy (A.S.P., M.J.K.), and Department of Physiology and Functional Genomics, College of Medicine (M.T.N., M.K.R.), University of Florida, Gainesville, Fla.
Correspondence to Mohan K. Raizada, PhD, Department of Physiology and Functional Genomics, PO Box 100274, University of Florida, College of Medicine, Gainesville, FL 32610. E-mail mraizada{at}phys.med.ufl.edu
Our studies have established that a single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense gene causes prolonged antihypertensive actions in the spontaneously hypertensive rat. These results suggest that antisense gene therapy is a conceptually valid strategy for the control of hypertension at the genetic level. To evaluate whether attenuation of the pathophysiological aspects of hypertension are dependent on the blood pressure lowering actions of antisense gene therapy, we chose the renin transgenic rat as a hypertensive animal model and cardiac hypertrophy as the hypertension-associated pathophysiology. A single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense in the neonatal rat resulted in long-term expression of the antisense transgene in various cardiovascular-relevant tissues, including the heart. This expression was associated with a significant attenuation of cardiac hypertrophy despite its failure to normalize high blood pressure. Developmental studies indicated that cardiac hypertrophy was evident as early as 16 days of age in viral vector–treated control transgenic rats, despite these animals exhibiting normal blood pressure. These observations demonstrate that, in the renin-transgenic rat, the onset of cardiac hypertrophy occurs during development and is prevented without normalization of high blood pressure. Collectively, these results provide further proof of the concept and indicate that antisense gene therapy could successfully target the local tissues’ renin-angiotensin system to produce beneficial cardiovascular outcomes.
Key Words: antisense elements • rat, transgenic • renin-angiotensin system • hypertension, essential • genes
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