C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells
C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells
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DOI：
10.1161/01.cir.0000136999.77584.a2
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发表时间：
2004-08-03
期刊：
影响因子：
37.8
通讯作者：
Law, RE
中科院分区：
文献类型：
--
作者：
Blaschke, F;Bruemmer, D;Law, RE
背景-越来越多的证据表明，C反应蛋白（CRP）除了是冠状动脉事件的预测因子外，还可能在动脉粥样硬化的演变中对血管壁有直接作用。虽然血管平滑肌细胞（VSMCs）在内膜中的积累是动脉病变发展的关键事件，但VSMCs的凋亡在动脉粥样硬化病变的进展中也起着重要作用，并导致斑块易损性增加。方法和结果-在本研究中，我们证明CRP诱导半胱天冬酶介导的人冠状动脉VSMCs凋亡。DNA微阵列分析用于鉴定CRP调控基因。CRP显著上调生长停滞和DNA损伤诱导基因153（GADD 153）mRNA表达。北方印迹分析证实，CRP诱导GADD 153 mRNA表达的时间和剂量依赖性增加。GADD 153是一个参与血管和非血管细胞生长停滞和凋亡的基因，在转录和转录后水平受到调控。CRP对VSMC中GADD 153 mRNA表达的调节主要通过mRNA稳定化在转录后水平发生。特异性靶向GADD 153的小干扰RNA（siRNA）减少CRP诱导的细胞凋亡。GADD 153还特异性共定位于人冠状动脉病变中的凋亡VSMC，进一步支持GADD 153在CRP诱导的细胞死亡中的功能作用。结论-这些结果表明，GADD 153是一个CRP调控的基因在人类血管平滑肌细胞和发挥因果作用CRP诱导的细胞凋亡。CRP表达或作用的药理学靶向可能为动脉粥样硬化提供新的治疗方法。
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.