Inducible cAMP early repressor inhibits growth of vascular smooth muscle cell
Inducible cAMP early repressor inhibits growth of vascular smooth muscle cell
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DOI：
10.1161/atvbaha.107.145011
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发表时间：
2007-07-01
影响因子：
8.7
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Ohtsubo, Hideki;Ichiki, Toshihiro;Sunagawa, Kenji
目的：诱导性cAMP早期抑制因子（ICER），一种转录抑制因子，在血管重构过程中的作用尚未确定。我们研究了ICER是否影响血管平滑肌细胞（VSMCs）的生长。方法与结果-半定量RT- PCR和Western blot分析显示，在贝拉普罗斯特（前列腺素I-2类似物）刺激的VSMCs中，ICER的表达呈时间和剂量依赖性增加。蛋白激酶a （PKA）抑制剂H89预处理可抑制ICER的表达，提示PKA介导了ICER表达的诱导。贝拉前列素抑制血小板源性生长因子诱导的胸腺嘧啶在VSMCs中的掺入，这种抑制作用可通过转染短干扰RNA而非scramble RNA来逆转。与LacZ过表达相比，腺病毒载体过表达ICER可使新内膜形成（内膜/介质比率）减少50%。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞数量增加，Ki- 67阳性细胞数量减少。结论- ICER诱导VSMC细胞凋亡，抑制VSMC细胞增殖，在贝拉前列素介导的VSMC细胞增殖抑制中起关键作用。ICER可能是一种重要的内源性血管增殖抑制剂。
Objective - The role of inducible cAMP early repressor ( ICER), a transcriptional repressor, in the vascular remodeling process has not been determined. We examined whether ICER affects growth of vascular smooth muscle cells ( VSMCs).Methods and Results - Semi- quantitative RT- PCR and Western blot analysis showed that expression of ICER was increased in beraprost ( a prostaglandin I-2 analogue)- stimulated VSMCs in a time- and dose- dependent manner. The induction of ICER was inhibited by pretreatment with H89, a protein kinase A ( PKA) inhibitor, suggesting that PKA mediates the induction of ICER expression. Beraprost suppressed platelet- derived growth factor - induced thymidine incorporation in VSMCs, which was reversed by transfection of short interfering RNA for ICER, not by scramble RNA. Overexpression of ICER by an adenovirus vector attenuated neointimal formation ( intima/ media ratio) by 50% compared with overexpression of LacZ. The number of terminal deoxynucleotidyl transferase- mediated dUTP nick end- labeling - positive cells was increased and the number of Ki- 67 - positive cells was decreased in ICER- transduced artery.Conclusion - These results suggest that ICER induces apoptosis and inhibits proliferation of VSMCs, and plays a critical role in beraprost- mediated suppression of VSMC proliferation. ICER may be an important endogenous inhibitor of vascular proliferation.