Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling
Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling
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DOI：
10.1074/jbc.m800021200
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发表时间：
2008-05-30
影响因子：
4.8
通讯作者：
Chen, Yabing
中科院分区：
文献类型：
--
作者：
Byon, Chang Hyun;Javed, Amjad;Chen, Yabing
氧化应激在动脉粥样硬化的发病机制中起着关键作用，包括高脂巨噬细胞的形成和炎症的发展。然而，氧化应激诱导的调节血管钙化发展的分子信号尚未被深入研究。血管平滑肌细胞(VSMC)的成骨分化在动脉粥样硬化病变的钙化过程中起着至关重要的作用。动脉粥样硬化病变中氧化应激的一个重要因素是血管细胞中来自不同来源的过氧化氢的形成。在这项研究中，我们定义了在H_2O_2诱导的VSMC钙化中起作用的分子信号。我们发现过氧化氢促进VSMC从收缩表型到成骨表型的表型转换。这种反应与成骨分化的关键转录因子Runx2的表达和反式激活有关。Runx2的缺失和过表达进一步证实了Runx2在氧化应激诱导的VSMC钙化中的重要作用。短发夹状RNA抑制Runx2可阻断VSMC钙化，腺病毒介导的Runx2单独过表达可诱导VSMC钙化。抑制H_2O_2激活的AKT信号通路可同时阻断VSMC钙化和Runx2的诱导。这种阻断作用不会引起VSMC的凋亡。综上所述，我们的数据显示了AKT介导的Runx2在氧化应激诱导的VSMC钙化中的关键作用。
Oxidative stress plays a critical role in the pathogenesis of atherosclerosis including the formation of lipid laden macrophages and the development of inflammation. However, oxidative stress-induced molecular signaling that regulates the development of vascular calcification has not been investigated in depth. Osteogenic differentiation of vascular smooth muscle cells (VSMC) is critical in the development of calcification in atherosclerotic lesions. An important contributor to oxidative stress in atherosclerotic lesions is the formation of hydrogen peroxide from diverse sources in vascular cells. In this study we defined molecular signaling that is operative in the H2O2-induced VSMC calcification. We found that H2O2 promotes a phenotypic switch of VSMC from contractile to osteogenic phenotype. This response was associated with an increased expression and transactivity of Runx2, a key transcription factor for osteogenic differentiation. The essential role of Runx2 in oxidative stress-induced VSMC calcification was further confirmed by Runx2 depletion and overexpression. Inhibition of Runx2 using short hairpin RNA blocked VSMC calcification, and adenovirus-mediated overexpression of Runx2 alone induced VSMC calcification. Inhibition of H2O2-activated AKT signaling blocked VSMC calcification and Runx2 induction concurrently. This blockage did not cause VSMC apoptosis. Taken together, our data demonstrate a critical role for AKT-mediated induction of Runx2 in oxidative stress-induced VSMC calcification.