Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling
Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling
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DOI：
10.1161/hypertensionaha.110.149781
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发表时间：
2010-08-01
期刊：
影响因子：
8.3
通讯作者：
Rakugi, Hiromi
中科院分区：
文献类型：
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作者：
Kaimoto, Taeko;Yasuda, Osamu;Rakugi, Hiromi
钙是控制血管平滑肌细胞(VSMC)收缩、增殖和分化的重要信号分子。在此，我们证明了钙拮抗剂硝苯地平在体外和体内都能抑制VSMC的去分化。将培养在层粘连蛋白涂层培养皿上的分化的VSMCs转移到无层粘连蛋白的培养皿中诱导去分化。诱导去分化导致非肌型肌球蛋白重链表达上调，肌球蛋白重链表达下调，肌球蛋白重链表达下调。硝苯地平显著抑制这些细胞中这些表型改变的诱导和Akt信号的上调。给予不影响血压的低浓度硝苯地平可抑制大鼠球囊损伤模型中非肌球蛋白重链表达的增加和肌球蛋白重链表达的减少。此外，硝苯地平还能抑制新生内膜的增殖和Akt信号的上调。然而，在硝苯地平处理的大鼠再生动脉内皮细胞中，磷酸化Akt的表达并未受到抑制。显性-负性Akt信号下调对血管内膜VSMC脱分化的抑制作用与硝苯地平相同。相反，通过将Akt信号上调入具有结构活性的Akt的细胞，可逆转硝苯地平对VSMC去分化的抑制作用。结论：硝苯地平通过抑制Akt信号通路抑制VSMC去分化，从而防止新生内膜增厚。(高血压。2010；56：247-252。)
Calcium is an essential signaling molecule that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and differentiation. Here, we show that the calcium antagonist nifedipine inhibits VSMC dedifferentiation in vitro and in vivo. Differentiated VSMCs cultured on laminin-coated dishes were transferred to laminin-free dishes to induce dedifferentiation. Induction of dedifferentiation resulted in the upregulation of nonmuscle myosin heavy chain expression, a marker of dedifferentiation, and the downregulation of smooth muscle myosin heavy chain expression, a marker of differentiation. Nifedipine significantly inhibited both the induction of these phenotypic changes and upregulation of Akt signaling in these cells. Administration of nifedipine at a low concentration that did not affect blood pressure could inhibit the increase in nonmuscle myosin heavy chain expression and decrease in smooth muscle myosin heavy chain expression in a rat balloon-injury model. Furthermore, nifedipine suppressed neointimal hyperplasia and upregulation of Akt signaling. However, phospho-Akt expression was not suppressed in the regenerating arterial endothelium of the nifedipine-treated rats. The inhibitory effect of the downregulation of Akt signaling by dominant-negative Akt on the induction of VSMC dedifferentiation in the intima was identical to that of nifedipine. In contrast, upregulation of Akt signaling by transfection of the cells with a constitutively active Akt reversed the nifedipine-induced inhibition of VSMC dedifferentiation. In conclusion, nifedipine inhibits VSMC dedifferentiation by suppressing Akt signaling, thereby preventing neointimal thickening. (Hypertension. 2010;56:247-252.)