Succinobucol induces apoptosis in vascular smooth muscle cells
Succinobucol induces apoptosis in vascular smooth muscle cells
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DOI：
10.1016/j.freeradbiomed.2011.11.029
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发表时间：
2012-03-01
影响因子：
7.4
通讯作者：
Stocker, Roland
中科院分区：
文献类型：
--
作者：
Midwinter, Robyn G.;Maghzal, Ghassan J.;Stocker, Roland
普罗布考在体外和体内抑制血管平滑肌细胞的增殖，并且该药物通过诱导血红素加氧酶-1（HO-1）来减少动物的内膜增生和动脉粥样硬化。因为普罗布考的琥珀酰酯，琥珀布考，最近作为一种抗动脉粥样硬化药物在人类中失败，我们研究了它对平滑肌细胞增殖的影响。丁二酚和普罗布考诱导大鼠主动脉平滑肌细胞HO-1和细胞增殖。然而，尽管HO-1的抑制逆转了普罗布考的抗增殖作用，但在琥珀布考中没有观察到这一点。相反，琥珀丁酚，而不是普罗布考诱导半胱天冬酶的活性和细胞凋亡，它增加了线粒体氧化氢乙啶乙锭，暗示的H2 O2和细胞色素c的参与。此外，琥珀丁酚，而不是普罗布考转换成过氧化物酶的细胞色素c在过氧化氢的存在下，琥珀丁酚诱导的细胞凋亡减少细胞缺乏细胞色素c或功能性线粒体复合物II。此外，琥珀酸可增加体内球囊血管成形术介导的血管损伤后血管平滑肌细胞的凋亡。我们的研究结果表明，succinobucol诱导细胞凋亡，通过涉及线粒体复合物II，H2 O2，和细胞色素c的途径。这些意想不到的结果进行了讨论，在光的琥珀丁二醇作为一种抗动脉粥样硬化药物在人类中的失败。(C)2011 Elsevier Inc. All rights reserved.
Probucol inhibits the proliferation of vascular smooth muscle cells in vitro and in vivo, and the drug reduces intimal hyperplasia and atherosclerosis in animals via induction of heme oxygenase-1 (HO-1). Because the succinyl ester of probucol, succinobucol, recently failed as an antiatherogenic drug in humans, we investigated its effects on smooth muscle cell proliferation. Succinobucol and probucol induced HO-1 and decreased cell proliferation in rat aortic smooth muscle cells. However, whereas inhibition of HO-1 reversed the antiproliferative effects of probucol, this was not observed with succinobucol. Instead, succinobucol but not probucol induced caspase activity and apoptosis, and it increased mitochondrial oxidation of hydroethidine to ethidium, suggestive of the participation of H2O2 and cytochrome c. Also, succinobucol but not probucol converted cytochrome c into a peroxidase in the presence of H2O2, and succinobucol-induced apoptosis was decreased in cells that lacked cytochrome c or a functional mitochondrial complex II. In addition, succinobucol increased apoptosis of vascular smooth muscle cells in vivo after balloon angioplasty-mediated vascular injury. Our results suggest that succinobucol induces apoptosis via a pathway involving mitochondrial complex II, H2O2, and cytochrome c. These unexpected results are discussed in light of the failure of succinobucol as an antiatherogenic drug in humans. (C) 2011 Elsevier Inc. All rights reserved.