Hypoxia-Induced Mitogenic Factor Promotes Cardiac Hypertrophy via Calcium-Dependent and Hypoxia-Inducible Factor-1 Mechanisms
Hypoxia-Induced Mitogenic Factor Promotes Cardiac Hypertrophy via Calcium-Dependent and Hypoxia-Inducible Factor-1 Mechanisms
复制标题
缺氧诱导的有丝分裂因子通过钙依赖性和缺氧诱导因子 1 机制促进心脏肥大
DOI：
10.1161/hypertensionaha.118.10845
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发表时间：
2018-08-01
期刊：
影响因子：
8.3
通讯作者：
Liu, Jie
中科院分区：
文献类型：
--
作者：
Kumar, Santosh;Wang, Gang;Liu, Jie
缺氧诱导有丝分裂因子（HIMF，又称炎症区发现蛋白1/抵抗素样蛋白）是一种分泌型且类似细胞因子的蛋白质，是缺氧诱导的肺动脉高压的关键刺激因子。鉴于HIMF在心脏疾病中的作用尚不明确，我们通过在心肌细胞中过表达和敲低HIMF，并对HIMF基因（himf）敲除小鼠进行特征分析，来探究HIMF在心肌肥大中可能发挥的作用。我们发现，在苯肾上腺素刺激诱导的心肌细胞肥大以及我们构建的经腹主动脉缩窄诱导的心肌肥大小鼠模型中，还有在扩张型心肌病患者的心脏中，HIMF的信使核糖核酸（mRNA）和蛋白质水平均上调。此外，与对照组相比，HIMF过表达可诱导心肌细胞肥大，表现为肥大生物标志物（心房利钠肽[ANP]和β - 肌球蛋白重链[β - MHC]）的蛋白表达升高以及细胞表面积增大。相反，敲低HIMF可预防苯肾上腺素诱导的心肌细胞肥大，且敲除小鼠中himf基因缺失显著减轻了腹主动脉缩窄诱导的肥大重塑和心脏功能障碍。HIMF过表达会增加胞质Ca²⁺浓度，并激活钙调神经磷酸酶 - 活化T细胞核因子（CaN - NFAT）和丝裂原活化蛋白激酶（MAPK）信号通路；而使用L型Ca²⁺通道阻滞剂硝苯地平降低胞质Ca²⁺浓度，或使用Calhex 231抑制钙敏感受体（CaSR），则可阻止这种效应。此外，HIMF过表达会增加新生大鼠心室肌细胞中缺氧诱导因子 - 1（HIF - 1）的表达，而HIMF基因敲除则抑制了腹主动脉缩窄小鼠中HIF - 1的上调。敲低HIF - 1可减轻HIMF诱导的心肌细胞肥大。总之，HIMF在心肌肥大的发生发展中起着关键作用，以HIMF为靶点可能是一种潜在的治疗策略。
HIMF (hypoxia-induced mitogenic factor/found in inflammatory zone 1/resistin like ) is a secretory and cytokine-like protein and serves as a critical stimulator of hypoxia-induced pulmonary hypertension. With a role for HIMF in heart disease unknown, we explored the possible roles for HIMF in cardiac hypertrophy by overexpressing and knocking down HIMF in cardiomyocytes and characterizing HIMF gene (himf) knockout mice. We found that HIMF mRNA and protein levels were upregulated in phenylephrine-stimulated cardiomyocyte hypertrophy and our mouse model of transverse aortic constriction-induced cardiac hypertrophy, as well as in human hearts with dilated cardiomyopathy. Furthermore, HIMF overexpression could induce cardiomyocyte hypertrophy, as characterized by elevated protein expression of hypertrophic biomarkers (ANP [atrial natriuretic peptide] and -MHC [myosin heavy chain-]) and increased cell-surface area compared with controls. Conversely, HIMF knockdown prevented phenylephrine-induced cardiomyocyte hypertrophy and himf ablation in knockout mice significantly attenuated transverse aortic constriction-induced hypertrophic remodeling and cardiac dysfunction. HIMF overexpression increased the cytosolic Ca2+ concentration and activated the CaN-NFAT (calcineurin-nuclear factor of activated T cell) and MAPK (mitogen-activated protein kinase) pathways; this effect could be prevented by reducing cytosolic Ca2+ concentration with L-type Ca2+ channel blocker nifedipine or inhibiting the CaSR (Ca2+ sensing receptor) with Calhex 231. Furthermore, HIMF overexpression increased HIF-1 (hypoxia-inducible factor) expression in neonatal rat ventricular myocytes, and HIMF knockout inhibited HIF-1 upregulation in transverse aortic constriction mice. Knockdown of HIF-1 attenuated HIMF-induced cardiomyocyte hypertrophy. In conclusion, HIMF has a critical role in the development of cardiac hypertrophy, and targeting HIMF may represent a potential therapeutic strategy.