Published online before print July 26, 2004, doi: 10.1161/01.CIR.0000136999.77584.A2
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(Circulation. 2004;110:579-587.)
© 2004 American Heart Association, Inc.
Original Articles |
C-Reactive Protein Induces Apoptosis in Human Coronary Vascular Smooth Muscle Cells
From the Division of Endocrinology, Diabetes, and Hypertension (F.B., D.B., F.Y., Y.T., W.W., W.H., R.E.L.), and Department of Pathology (M.C.F.), David Geffen School of Medicine, University of California, Los Angeles; Department of Medicine/Cardiology, German Heart Institute, Berlin, Germany (F.B., K.G., E.F.); and Second Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan (Y.T., T.O., J.H.).
Correspondence to Willa A. Hsueh, MD, Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095. E-mail whsueh{at}mednet.ucla.edu
Received October 2, 2003; de novo received February 13, 2004; revision received April 13, 2004; accepted April 21, 2004.
Background— Accumulating evidence suggests that C-reactive protein (CRP), in addition to being a predictor of coronary events, may have direct actions on the vessel wall in the evolution of atherosclerosis. Although accumulation of vascular smooth muscle cells (VSMCs) in the intima is a key event in the development of arterial lesions, apoptosis of VSMCs also plays an important role in progression of atherosclerotic lesions and contributes to increased plaque vulnerability.
Methods and Results— In the present study we demonstrate that CRP induces caspase-mediated apoptosis of human coronary VSMCs. DNA microarray analysis was used to identify CRP-regulated genes. The growth arrest– and DNA damage–inducible gene 153 (GADD153) mRNA expression was prominently upregulated by CRP. As confirmed by Northern blot analysis, CRP induced a time- and dose-dependent increase of GADD153 mRNA expression. GADD153, a gene involved in growth arrest and apoptosis in vascular and nonvascular cells, is regulated at both transcriptional and posttranscriptional levels. CRP regulation of GADD153 mRNA expression in VSMCs occurs primarily at the posttranscriptional level by mRNA stabilization. Small interfering RNA (siRNA) specifically targeted to GADD153 reduced CRP-induced apoptosis. GADD153 also specifically colocalized to apoptotic VSMCs in human coronary lesions, further supporting a functional role for GADD153 in CRP-induced cell death.
Conclusions— These results demonstrate that GADD153 is a CRP-regulated gene in human VSMCs and plays a causal role in CRP-induced apoptosis. Pharmacological targeting of CRP expression or action may provide a novel therapy for atherosclerosis.
Key Words: C-reactive protein • apoptosis • transcription factors • muscle, smooth, vascular
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