Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling
Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling
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Nesfatin-1 在高血压血管重塑中充当 VSMC 表型转化和增殖的开关
DOI：
10.1016/j.bbadis.2018.04.002
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发表时间：
2018-06-01
影响因子：
6.2
通讯作者：
Sun, Hai-Jian
中科院分区：
文献类型：
--
作者：
Lu, Qing-Bo;Wang, Hui-Ping;Sun, Hai-Jian
在包括高血压在内的许多心血管疾病中，血管平滑肌细胞（VSMC）从分化到去分化的表型转化在VSMC增殖和血管重塑中起着至关重要的作用。Nesfatin-1是一种多功能脂肪细胞因子，在血压调节中起着重要作用。然而，nesfatin-1是否是高血压VSMC表型转换和增殖的潜在候选者仍有待研究。实验在Wistar-Kyoto大鼠（WKY）、自发性高血压大鼠（SHR）、人VSMCs和原代大鼠主动脉VSMCs中进行。我们发现nesfatin-1在SHR和SHR衍生的VSMCs的主动脉中层中的表达上调。Nesfatin-1促进VSMC表型转化，加速细胞周期进程和增殖。敲低nesfatin-1抑制VSMC表型从收缩状态转换为合成状态，减弱细胞周期进程，延缓SHR衍生的VSMC增殖。JAK/STAT抑制剂WP 1066可阻断nesfatin-1激活的PI 3 K/Akt/mTOR信号通路，抑制PI 3 K/Akt/mTOR可抑制Nesfatin-1诱导的JAK 2/STAT 3磷酸化水平升高。阻断PI 3 K/Akt/mTOR和JAK 2/STAT 3之间形成的反馈环可抑制nesfatin-1孵育的VSMCs和SHR原代VSMCs的增殖。慢性腹腔注射nesfatin-1可引起正常大鼠严重的高血压和心血管重构。相反，沉默nesfatin-1基因可改善SHR的高血压、表型转换和主动脉血管重塑。因此，我们的数据确定nesfatin-1作为高血压和血管重塑的关键调节剂，通过促进VSMC表型转换和增殖。
The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.