From the Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology (S.K., G.W., W.C., J.L.), Shenzhen University Health Science Center, China.
Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology (N.Z.), Shenzhen University Health Science Center, China.
Hypertension. 2019 May;73(5):1058-1070. doi: 10.1161/HYPERTENSIONAHA.118.12267.
HIMF (hypoxia-induced mitogenic factor) is a secreted proinflammatory cytokine with a critical role in cardiac hypertrophy development. Loss of HIMF attenuates transverse aortic constriction-induced cardiac hypertrophy and fibrosis, but the underlying mechanisms are unknown. We show that IL (interleukin)-6 production increases following transverse aortic constriction in wild-type mice; this effect is inhibited in HIMF gene knockout ( Himf) mice. IL-6 production also increases in cultured cardiac myocytes overexpressing HIMF and neutralizing IL-6 with an anti-IL-6 antibody prohibits HIMF-induced cardiomyocyte hypertrophy. HIMF expression in cardiac fibroblasts cannot be stimulated by transverse aortic constriction or exposure to prohypertrophic factors, including phenylephrine, Ang II (angiotensin II), TGF (transform growth factor)-β, and hypoxia. However, conditioned medium from cardiomyocytes overexpressing HIMF can increase IL-6 production, and cardiac fibroblast proliferation, migration, and myofibroblast differentiation to a similar level as exposure to exogenous rHIMF (recombinant HIMF). Again, neutralizing IL-6 prevented cardiac fibroblasts activation. Finally, the MAPK (mitogen-activated protein kinase) and CaMKII (Ca/calmodulin-dependent protein kinase II)-STAT3 (signal transducers and activators of transcription 3) pathways are activated in HIMF-overexpressing cardiomyocytes and rHIMF-stimulated cardiac fibroblasts; this effect can be inhibited on neutralizing IL-6. These data support that HIMF induces cardiac fibrosis via a cardiomyocyte-to-fibroblast paracrine effect. IL-6 is a downstream signal of HIMF and has a central role in cardiomyocyte hypertrophy and myocardial fibrosis that is mediated by activating the MAPK and CaMKII-STAT3 pathways.
HIMF（缺氧诱导的有丝分裂因子）是一种分泌的促炎细胞因子，在心脏肥大发展中起关键作用。HIMF 的缺失可减轻主动脉缩窄引起的心脏肥大和纤维化，但具体机制尚不清楚。我们发现，在野生型小鼠中，主动脉缩窄后白细胞介素（IL）-6 的产生增加；这种效应在 HIMF 基因敲除（HIMF）小鼠中被抑制。在过表达 HIMF 的心肌细胞培养物中，IL-6 的产生也会增加，而用抗 IL-6 抗体中和 IL-6 则可阻止 HIMF 诱导的心肌细胞肥大。心脏成纤维细胞中的 HIMF 表达不能被主动脉缩窄或暴露于促肥大因子（包括苯肾上腺素、血管紧张素 II（Ang II）、转化生长因子-β和缺氧）所刺激。然而，过表达 HIMF 的心肌细胞的条件培养基可以增加 IL-6 的产生，以及心脏成纤维细胞的增殖、迁移和向肌成纤维细胞分化，达到与外源性 rHIMF（重组 HIMF）暴露相似的水平。同样，中和 IL-6 可防止心脏成纤维细胞的激活。最后，在过表达 HIMF 的心肌细胞和 rHIMF 刺激的心脏成纤维细胞中，MAPK（丝裂原激活的蛋白激酶）和 CaMKII（钙/钙调蛋白依赖性蛋白激酶 II）-STAT3（信号转导和转录激活因子 3）途径被激活；这种效应可以通过中和 IL-6 来抑制。这些数据支持 HIMF 通过心肌细胞到成纤维细胞的旁分泌作用诱导心脏纤维化。IL-6 是 HIMF 的下游信号，在心肌细胞肥大和心肌纤维化中起核心作用，其介导途径是激活 MAPK 和 CaMKII-STAT3 途径。
