Acetylbritannilactone induces G1 arrest and apoptosis in vascular smooth muscle cells.
Acetylbritannilactone induces G1 arrest and apoptosis in vascular smooth muscle cells.
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DOI：
10.1016/j.ijcard.2009.11.036
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发表时间：
2011-05
影响因子：
3.5
通讯作者：
B. Liu;Mei Han;Rong‐hua Sun;Jun-jie Wang;Yueping Liu;J. Wen
中科院分区：
文献类型：
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作者：
B. Liu;Mei Han;Rong‐hua Sun;Jun-jie Wang;Yueping Liu;J. Wen
本研究旨在研究天然大不列颠菊属植物乙酰不列颠内酯（ABL）对血管平滑肌细胞（VSMC）增殖和凋亡的影响。方法采用体外实验研究ABL对化学引诱剂刺激VSMC周期和细胞凋亡的影响。此外，为了研究ABL在体内的作用，我们对大鼠颈动脉进行了球囊损伤。结果abl抑制血小板源性生长因子（PDGF）诱导的VSMC DNA合成和增殖。ABL的这种生长抑制作用与g1期阻滞有关，与细胞周期蛋白D1、A、E表达和细胞周期蛋白依赖性激酶（CDK） 2、CDK4、CDK6蛋白表达减少有关，增加了CDK抑制蛋白p21cip1的表达，增强了p21cip1与CDKs的结合。此外，ABL还能诱导增殖性VSMCs的凋亡，如诱导Bax/Bcl-2比例升高，激活caspase-9、caspase-3，以及内源性底物聚（adp -核糖）聚合酶的裂解。然而，使用pan-caspases inhibitor （z-VAD-fmk）预处理只能部分逆转abl诱导的细胞凋亡，这表明caspase依赖性和caspase非依赖性通路都参与了这些过程。此外，ABL对VSMCs的影响与下调细胞外信号调节激酶（ERK） 1/2信号通路有关。在体内，ABL （26mg/kg/天）显著抑制损伤诱导的ERK1/2磷酸化，并增加球囊损伤后14天VSMC凋亡。结论ABL在体内和体外均能抑制VSMC异常增殖，并诱导细胞凋亡。提示ABL可被认为是预防球囊血管成形术后再狭窄的药理学候选药物。
BACKGROUNDThe present study was designed to determine the effects of Acetylbritannilactone (ABL), a naturally occurring Inula britannica L., on vascular smooth muscle cell (VSMC) proliferation and apoptosis.METHODSIn vitro experiments were performed to evaluate the effects of ABL on the VSMC cycle and apoptosis stimulated by chemoattractant. In addition, to examine the effects of ABL in vivo, balloon injury to rat carotid arteries was performed.RESULTSABL treatment inhibited platelet-derived growth factor (PDGF) induced DNA synthesis and proliferation in cultured VSMC. Such growth-inhibitory effects of ABL were associated with G1phase arrest, which were correlated with reduction of cyclins D1, A, and E expression and cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 proteins, increased the CDK inhibitory protein p21cip1expression, and enhanced the binding of p21cip1to CDKs. In addition, ABL also induced apoptosis in proliferative VSMCs, as evidenced by the induction of a higher ratio of Bax/Bcl-2, activation of caspase-9, caspase-3, and the cleavage of endogenous substrate Poly (ADP-ribose) polymerase. However, pretreatment with pan-caspases inhibitor (z-VAD-fmk) only partially reversed ABL-induced apoptosis, suggesting the involvement of both caspase-dependent and caspase-independent pathways in these processes. Furthermore, the effects of ABL on VSMCs were associated with the downregulation of extracellular signal-regulated kinase (ERK) 1/2 signaling pathways. In vivo, ABL (26mg/kg/day) significantly suppressed injury-induced ERK1/2 phosphorylation, and increased VSMC apoptosis 14days after balloon injury.CONCLUSIONSOur findings demonstrated that ABL was capable of suppressing the abnormal VSMC proliferation, accompanied by the induction of apoptosis in vivo and in vitro. It suggested that ABL could be considered a pharmacological candidate for the prevention of restenosis after balloon angioplasty.