C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells.
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.


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.
Blaschke
Florian
F
Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Bruemmer
Dennis
D
Yin
Fen
F
Takata
Yasunori
Y
Wang
Wei
W
Fishbein
Michael C
MC
Okura
Takafumi
T
Higaki
Jitsuo
J
Graf
Kristof
K
Fleck
Eckart
E
Hsueh
Willa A
WA
Law
Ronald E
RE
D017209:Apoptosis / Q000187:drug effects*; D002097:C-Reactive Protein / Q000494:pharmacology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013268:Stimulation, Chemical
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002097:C-Reactive Protein