(Hypertension. 1999;33:162-166.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Interferon Regulatory Factors Regulate Interleukin-1ß–Converting Enzyme Expression and Apoptosis in Vascular Smooth Muscle Cells
From Cardiovascular Research, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
Correspondence to Masatsugu Horiuchi, MD, PhD, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Thorn-13, Boston, MA 02115. E-mail mhoriuch{at}rics.bwh.harvard.edu
Abstract—Apoptosis has been reported to play a pivotal role in vascular remodeling. However, cellular mechanisms of apoptosis in vascular smooth muscle cells (VSMCs) have not been well defined. In this study, we focused on interleukin-1ß–converting enzyme (ICE), a key protease in the induction of apoptosis in lymphocytes and fibroblasts. We observed an increase in ICE mRNA expression in rat aortic VSMCs after serum depletion, with a peak at 12 hours and then a gradual decline. This was associated with DNA fragmentation, a hallmark of apoptosis and morphological changes of apoptosis. Treatment of these VSMCs with the ICE inhibitor N-(N-acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid (YVAD-CHO) attenuated DNA fragmentation. The increased ICE mRNA expression was preceded by an increase in the mRNA expression of interferon regulatory factor (IRF)-1, peaking at 6 hours after serum removal, and a rapid but transient decrease in IRF-2 mRNA expression, reaching a nadir at 3 hours after serum depletion. To demonstrate that these reciprocal changes in IRF-1 and IRF-2 regulated ICE expression and induced apoptosis, we transfected antisense oligonucleotides for IRF-1 and IRF-2 into VSMCs and examined ICE mRNA expression and apoptotic changes. IRF-1 antisense pretreatment attenuated the increase in ICE expression and reduced apoptotic changes, whereas IRF-2 antisense treatment increased ICE mRNA expression and enhanced apoptotic changes. Taken together, our results suggest that serum growth factor depletion in VSMCs upregulates IRF-1 and downregulates IRF-2, thereby increasing ICE expression and inducing apoptosis.
Key Words: apoptosis • growth substances • interferons • interleukin-1 • muscle, smooth, vascular
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