From the Department of Pathophysiology, Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, China (S.K., G.W., W.L., M.D., N.Z., J.L.).
Institute for Cancer Prevention and Treatment, School of Medicine, Jingchu University of Technology, Jingmen, China (W.D.).
Hypertension. 2018 Aug;72(2):331-342. doi: 10.1161/HYPERTENSIONAHA.118.10845. Epub 2018 Jun 11.
HIMF (hypoxia-induced mitogenic factor/found in inflammatory zone 1/resistin like α) 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 () 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 β-MHC [myosin heavy chain-β]) and increased cell-surface area compared with controls. Conversely, HIMF knockdown prevented phenylephrine-induced cardiomyocyte hypertrophy and ablation in knockout mice significantly attenuated transverse aortic constriction-induced hypertrophic remodeling and cardiac dysfunction. HIMF overexpression increased the cytosolic Ca 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 Ca concentration with L-type Ca channel blocker nifedipine or inhibiting the CaSR (Ca sensing receptor) with Calhex 231. Furthermore, HIMF overexpression increased HIF-1α (hypoxia-inducible factor) expression in neonatal rat ventricular myocytes, and HIMF knockout inhibited HIF-1α upregulation in transverse aortic constriction mice. Knockdown of HIF-1α 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.
HIMF（缺氧诱导的有丝分裂原因子/在炎症区 1 中发现/抵抗素样α）是一种分泌型细胞因子样蛋白，是缺氧诱导肺动脉高压的关键刺激因子。由于 HIMF 在心脏病中的作用尚不清楚，我们通过在心肌细胞中过表达和敲低 HIMF 并对 HIMF 基因（）敲除小鼠进行特征描述，来探索 HIMF 在心肌肥厚中的可能作用。我们发现，HIMF mRNA 和蛋白水平在苯肾上腺素刺激的心肌肥厚和我们的横主动脉缩窄诱导的心肌肥厚小鼠模型以及扩张型心肌病的人类心脏中均上调。此外，与对照相比，HIMF 过表达可诱导心肌细胞肥大，表现为肥大标志物（ANP[心房利钠肽]和β-MHC[肌球蛋白重链-β]）的蛋白表达升高和细胞表面积增加。相反，HIMF 敲低可预防苯肾上腺素诱导的心肌肥厚，而在敲除小鼠中消融可显著减轻横主动脉缩窄诱导的肥厚重塑和心脏功能障碍。HIMF 过表达增加了细胞质 Ca 浓度并激活了 CaN-NFAT（钙调神经磷酸酶-活化 T 细胞核因子）和 MAPK（丝裂原激活蛋白激酶）途径；通过用 L 型 Ca 通道阻滞剂硝苯地平降低细胞质 Ca 浓度或用 Calhex 231 抑制 CaSR（钙敏感受体）可以预防这种作用。此外，HIMF 过表达增加了新生大鼠心室肌细胞中的 HIF-1α（缺氧诱导因子）表达，而 HIMF 敲除抑制了横主动脉缩窄小鼠中 HIF-1α 的上调。HIF-1α 的敲低减弱了 HIMF 诱导的心肌肥厚。总之，HIMF 在心肌肥厚的发展中起着关键作用，靶向 HIMF 可能代表一种潜在的治疗策略。
