Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy
Abstract Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro . Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation. Highlights IL-6 deficiency alleviates cardiac fibrosis during AngII stimulation. IL-6 KO-AngII hearts exhibited decreased inflammation and apoptosis. Cardiac hypertrophy is provoked in IL-6 KO mice under AngII stimulation. IL-6/STAT3 regulates AngII-induced myocyte hypertrophy via EndoG/MEF2A pathway. Graphical abstract Schematic diagram showing the development of cardiomyopathy under the regulation of IL-6 during AngII-stimulation. During AngII stimulation, IL-6 expression increases in cardiomyocytes and activates STAT3. STAT3 phosphorylation promotes its nucleus translocation. On one hand, phosphorylated STAT3 (p-STAT3) facilitates the transcription of genes associated with inflammation; on the other hand, p-STAT3 also strengthens the inhibitory effect of EndoG on MEF2A, resulting in alleviated myocyte hypertrophy. AngII also affects the EndoG-MEF2A signaling pathway by inhibiting EndoG expression, causing increased cardiac hypertrophy. Moreover, AngII promotes myocardium apoptosis via upregulating the ratio of Bax/Bcl-2.Dashed arrows: our hypothesis in the study. [DISPLAY OMISSION]
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