(Hypertension. 1997;30:1035-1040.)
© 1997 American Heart Association, Inc.
Articles |
Effect of Nitric Oxide on DNA Replication Induced by Angiotensin II in Rat Cardiac Fibroblasts
From the Department of Biochemistry and The Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
Correspondence to Peter Brecher, PhD, Boston University School of Medicine, 80 East Concord St W507, Boston, MA 02118. E-mail pbrecher{at}acs.bu.edu
Abstract Our previous in vivo studies (Hou et al. J Clin Invest. 1995;96:2469-2477.) demonstrated that chronic inhibition of nitric oxide synthase led to an exaggerated response to relatively low doses of angiotensin II, resulting in a rapid and marked cardiac fibrosis. To examine further the importance of angiotensin II in inducing cardiac fibrosis and the possibility that nitric oxide serves as a modulator of the proliferative effects of angiotensin II, we used cultured rat cardiac fibroblasts to study the interrelationships between these substances. Angiotensin II induced a delayed DNA synthetic response in quiescent cells that occurred 30 hours after exposure to the hormone. The most pronounced effect of angiotensin II on thymidine uptake occurred 36 to 42 hours after the addition to cells. This response was inhibited in a dose-dependent manner by the addition of either S-nitroso-N-acetylpenicillamine or sodium nitroprusside, each a source of nitric oxide. The nitric oxide donor was most effective in reducing thymidine incorporation when added 12 hours after angiotensin II, whereas the metabolite N-acetylpenicillamine had no effect at any time. The inhibitory effect of S-nitroso-N-acetylpenicillamine was mimicked by 8-bromoguanosine 3':5'-cyclic monophosphate but not by 8-bromoadenosine 3':5'-cyclic monophosphate. Nitric oxide donors did not appear to inhibit the induction of c-fos, Egr-1, or other immediate-early genes in response to angiotensin II. The results suggest that nitric oxide affects the cell cycle following the transition into G1 and modulates the proliferation of fibroblasts during cardiac fibrosis induced by angiotensin II.
Key Words: cardiac fibrosis • fibroblasts • angiotensin II • nitric oxide • cell proliferation
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