Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell
Dynamin-2 regulates oxidized low-density lipoprotein-induced apoptosis of vascular smooth muscle cell
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DOI：
10.1161/01.cir.0000147828.86593.85
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发表时间：
2004-11-23
期刊：
影响因子：
37.8
通讯作者：
Daida, H
中科院分区：
文献类型：
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作者：
Kashiwakura, Y;Watanabe, M;Daida, H
氧化低密度脂蛋白（oxLDL）暴露后，血管细胞通常发生凋亡，这是动脉粥样硬化的主要致病因素之一。在这项研究中，我们研究了动力蛋白（一个重要的GT3蛋白的内吞作用）在oxLDL诱导的血管平滑肌细胞（VSMC）的凋亡的作用。方法和结果oxLDL刺激后，动力蛋白-2与LOX-1周围的细胞表面，以及oxLDL在细胞质中共定位，这表明，动力蛋白-2参与清道夫受体介导的oxLDL内吞作用。由动力蛋白-2显性负性质粒（K44 A）诱导的动力蛋白-2的下调导致oxLDL摄取的减少，从而导致细胞凋亡的减少。这些数据表明，dynamin-2参与oxLDL诱导的细胞凋亡通过oxLDL内吞途径。另一方面，动力蛋白-2野生型质粒转染促进oxLDL诱导的细胞凋亡，而不增加oxLDL的摄取。有趣的是，p53抑制剂pifithrin-alpha（PFT）显著降低了野生型发动蛋白-2促进的细胞凋亡（与PFT[-]条件相比降低了78%）。这些结果表明dynamin-2可能通过参与p53信号转导途径增强oxLDL诱导的VSMC凋亡。此外，我们证明，在先进的载脂蛋白E-/-小鼠斑块，发动蛋白-2表达往往在凋亡的VSMC增强，这表明发动蛋白-2可能参与VSMC的凋亡，即使在vivo.Conclusions -我们的数据表明，发动蛋白-2至少部分调节oxLDL诱导的VSMC凋亡，通过参与2个独立的途径：oxLDL内吞途径和p53途径。这些结果表明，dynamin-2可能作为一个新的研究或治疗血管疾病的目标。
Background-On exposure to oxidized low-density lipoprotein (oxLDL), vascular cells generally undergo apoptosis, which is one of the major pathogenic factors of atherosclerosis. In this study, we examined the role of dynamin ( a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC).Methods and Results-After oxLDL stimulation, dynamin-2 colocalized with LOX-1 around the cell surface, as well as oxLDL in the cytoplasm, suggesting that dynamin-2 was involved in scavenger receptor-mediated oxLDL endocytosis. Downregulation of dynamin-2 induced by dynamin-2 dominant negative plasmid (K44A) resulted in a decrease of oxLDL uptake and thereby in a reduction of apoptosis. These data demonstrated that dynamin-2 was involved in oxLDL-induced apoptosis via the oxLDL endocytotic pathway. On the other hand, dynamin-2 wild-type plasmid transfection promoted oxLDL-induced apoptosis without increasing oxLDL uptake. Interestingly, the p53 inhibitor pifithrin-alpha (PFT) significantly reduced apoptosis promoted by wild-type dynamin-2 (78% reduction compared with the PFT[-] condition). These results indicated that dynamin-2 enhanced oxLDL-induced apoptosis of VSMC by participating in the p53 pathway, probably as a signal transducer. Moreover, we demonstrated that, in advanced plaques of apolipoprotein E-/- mice, dynamin-2 expression was often enhanced in apoptotic VSMC, suggesting that dynamin-2 might participate in apoptosis of VSMC even in vivo.Conclusions - Our data demonstrated that dynamin-2 at least partially regulated oxLDL-induced apoptosis of VSMC by participating in 2 independent pathways: the oxLDL endocytotic pathway and the p53 pathway. These findings suggest that dynamin-2 may serve as a new research or therapeutic target in vascular disease.