Exercise Training Reverses Lipotoxicity-induced Cardiomyopathy by Inhibiting HMGCS2
Exercise Training Reverses Lipotoxicity-induced Cardiomyopathy by Inhibiting HMGCS2
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运动训练通过抑制 HMGCS2 逆转脂毒性诱发的心肌病
DOI：
10.1249/mss.0000000000002453
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发表时间：
2021-01-01
影响因子：
4.1
通讯作者：
Jiang, Songhe
中科院分区：
文献类型：
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作者：
Li, Shengcun;Qian, Xiaoli;Jiang, Songhe
目的探讨运动训练对脂毒性心肌病的预防作用，以及3-羟基-3-甲基戊二酰辅酶A合酶2（HMGCS 2）和miR-344 g-5 p在心肌细胞中的作用。方法雄性C57 BL/6小鼠喂饲60%高脂饲料12 wk后，开始游泳运动或保持安静8 wk。此后，通过超声心动图评估心脏功能，并收集心脏组织和血浆用于进一步测量。在棕榈酸诱导的新生小鼠心肌细胞中处理Hmgcs 2 siRNA后，研究运动的分子机制。结果HFD可导致心肌肥厚和纤维化，降低冠状动脉储备和心功能。HFD小鼠心脏中HMGCS 2水平升高，但JPH 2水平降低。这种影响被游泳运动减弱。从机制上讲，Hmgcs 2沉默阻止了棕榈酸刺激的心肌细胞凋亡和caspase-3裂解，并提高了JPH 2的表达。此外，运动促进了HFD心脏中miR-344 g-5 p的表达。在棕榈酸诱导的心肌细胞中，通过化学模拟物过表达miR-344 g-5 p减少了HMGCS 2、凋亡和caspase-3裂解，并升高了JPH 2表达。结论我们的研究结果表明，运动限制脂质代谢紊乱，心肌肥厚和纤维化，并有助于预防脂毒性心肌病。通过上调靶向Hmgcs 2 mRNA的miR-344 g-5 p，抑制HMGCS 2上调，从而抑制脂毒性。
PurposeThis study aimed to determine the effect of exercise training on preventing lipotoxic cardiomyopathy and to investigate the role of the 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and miR-344g-5p in cardiomyocytes. MethodsMale C57BL/6 mice were fed a 60% high-fat diet (HFD) for 12 wk then began swimming exercise or remained sedentary for 8 wk. Thereafter, cardiac function was assessed by echocardiography, and heart tissue and plasma were collected for further measurements. The molecular mechanism of exercise was investigated after treating Hmgcs2 siRNA in palmitate-induced neonatal mouse cardiomyocytes. ResultsHFD induced myocardial hypertrophy and fibrosis and reduced coronary reserve and cardiac function. HMGCS2 levels increased, but junctophilin-2 (JPH2) levels decreased in HFD mice hearts. Such effects were attenuated by swimming exercise. Mechanistically, Hmgcs2 silencing prevented apoptosis and caspase-3 cleavage and elevated the expression of JPH2 in palmitate-stimulated cardiomyocytes. In addition, exercise promoted miR-344g-5p expression in HFD hearts. The overexpression of miR-344g-5p by chemical mimic reduced HMGCS2, apoptosis, and caspase-3 cleavage and elevated JPH2 expression in palmitate-induced cardiomyocytes. ConclusionOur results suggest that exercise limits lipid metabolic disorder, cardiac hypertrophy, and fibrosis and aids in the prevention of lipotoxic cardiomyopathy. Exercise-mediated cardioprotection by upregulating miR-344g-5p, which targets Hmgcs2 mRNA, prohibits HMGCS2 upregulation and thus lipotoxicity.