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(Circulation Research. 1999;85:614-622.)
© 1999 American Heart Association, Inc.

Integrative Physiology

Sustained Inhibition of Angiotensin I–Converting Enzyme (ACE) Expression and Long-Term Antihypertensive Action by Virally Mediated Delivery of ACE Antisense cDNA

Hongwei Wang, Michael J. Katovich, Craig H. Gelband, Phyllis Y. Reaves, M. Ian Phillips, Mohan K. Raizada

From the Departments of Physiology (H.W., C.H.G., P.Y.R., M.I.P., M.K.R.) and Pharmacodynamics (M.J.K.), Colleges of Medicine and Pharmacy, and University of Florida Brain Institute, Gainesville, Fla.

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

Abstract—Angiotensin I–converting enzyme (ACE) inhibitors have been proven to be highly effective and are for the most part the drugs of choice in the treatment and control of hypertension, congestive heart failure, and left ventricular dysfunction. Despite this, questions regarding side effects and compliance with this traditional pharmacological strategy remain. In view of these observations, coupled with recent advances in gene-transfer technology, our objective in this study was to determine whether the expression of ACE could be controlled on a permanent basis at a genetic level. We argued that the introduction of ACE antisense to inhibit the enzyme would be a prerequisite in considering the antisense gene therapy for the control of hypertension and other related pathological states. Retroviral vectors (LNSV) containing ACE sense (LNSV-ACE-S) and ACE antisense (LNSV-ACE-AS) sequences were constructed and were used in rat pulmonary artery endothelial cells (RPAECs) to determine the feasibility of this approach. Infection of rat RPAECs with LNSV-ACE-S and LNSV-ACE-AS resulted in a robust expression of transcripts corresponding to ACE-S and ACE-AS, respectively, for the duration of these experiments, ie, 8 consecutive passages. The expression of ACE-AS but not of ACE-S was associated with a permanent decrease of 70% to 75% in ACE expression and a 50% increase in the B_max for the AT₁s. Although angiotensin II caused a concentration-dependent stimulation of intracellular Ca²⁺ levels in both ACE-S– and ACE-AS–expressing cells, the stimulation was significantly higher in ACE-AS–expressing RPAECs. In vivo experiments demonstrated a prolonged expression of ACE-AS transcripts in cardiovascularly relevant tissues of rats. This was associated with a long-term reduction in blood pressure by 15 mm Hg, exclusively in the spontaneously hypertensive rat. These observations demonstrate that delivery of ACE-AS by retroviral vector results in a permanent inhibition of ACE and a long-term reduction in high blood pressure in the spontaneously hypertensive rat.

Key Words: virally mediated delivery • angiotensin-converting enzyme inhibitor • endothelial cell • hypertension • gene therapy

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