Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase
Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase
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DOI：
10.1038/hr.2009.77
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发表时间：
2009-08-01
影响因子：
5.4
通讯作者：
Iwao, Hiroshi
中科院分区：
文献类型：
--
作者：
Izumi, Yasukatsu;Shiota, Masayuki;Iwao, Hiroshi
他汀类药物对心血管系统具有多效性，部分是通过增加一氧化氮(NO)的生物利用度来实现的。在这项研究中，我们研究了普伐他汀在缺血诱导的血管生成中的作用。手术诱导C57BL/6J小鼠单侧后肢缺血。缺血组织中AMP激活的蛋白激酶(AMPK)、乙酰辅酶A羧基酶(ACC)和内皮型一氧化氮合酶(ENOS)的磷酸化水平升高。此外，普伐他汀治疗的小鼠比未治疗的小鼠表现出更高的磷酸化增加。激光多普勒分析表明，普伐他汀治疗可加速侧支血管的发育和血管生成，以响应后肢缺血。普伐他汀治疗后，缺血后肢的毛细血管密度也增加。体外培养的人脐静脉内皮细胞(HUVECs)显示，普伐他汀可增加AMPK的磷酸化。AMPK受体拮抗剂化合物C可抑制普伐他汀诱导的eNOS的磷酸化。化合物C可显著抑制普伐他汀促进HUVECs的迁移和管状形成。经复方C治疗后，普伐他汀对后肢缺血后血管生成的促进作用明显减弱，从而在体内诱导AMPK的磷酸化。此外，普伐他汀在体内和体外也能激活AMPK。这种磷酸化导致eNOS激活和血管生成，这为他汀类药物有利于血管生成的多效性作用之一提供了新的解释。高血压研究(2009年)32675679；DOI：10.1038/hr.2009.77；2009年6月5日在线发布
Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. In this study, we examined the role of pravastatin in ischemia-induced angiogenesis. Unilateral hindlimb ischemia was surgically induced in C57BL/6J mice. Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and endothelial NO synthase (eNOS) was increased in ischemic tissues. Furthermore, mice treated with pravastatin showed higher increases in phosphorylation than did untreated mice. Laser Doppler analysis has shown that pravastatin treatment accelerates the development of collateral vessels and angiogenesis in response to hindlimb ischemia. Capillary density in the ischemic hindlimb was also increased by pravastatin treatment. An in vitro study on human umbilical vein endothelial cells (HUVECs) revealed that pravastatin increased the phosphorylation of AMPK. Pravastatin-induced phosphorylation of eNOS, one of the downstreams of AMPK, was inhibited by compound C, an AMPK antagonist. The increased migration and tube formation of HUVECs by pravastatin were significantly blocked by compound C treatment. The accelerated angiogenesis by pravastatin after hindlimb ischemia was significantly reduced after treatment with compound C. Thus, ischemia induced AMPK phosphorylation in vivo. Furthermore, pravastatin could also activate AMPK in vivo and in vitro. Such phosphorylation results in eNOS activation and angiogenesis, which provide a novel explanation for one of the pleiotropic effects of statins that is beneficial for angiogenesis. Hypertension Research (2009) 32, 675-679; doi:10.1038/hr.2009.77; published online 5 June 2009