Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890, Japan.
Department of Cardiology, Chi-Mei Medical Center, Yong Kang, Tainan City, 71003, Taiwan.
Sci Rep. 2019 Mar 6;9(1):3633. doi: 10.1038/s41598-019-40002-0.
Left ventricular hypertrophy is an independent risk factor in diabetic patients. TGR5 is shown to express in hearts, but its functional role in diabetes-induced cardiac hypertrophy remained unclear. The current study investigated the role of TGR5 on high glucose-induced hypertrophy of H9C2 cells. After incubation with a high level of glucose, H9C2 cells showed hypertrophic responses. Activation of TGR5 by lithocholic acid (LCA) ameliorated cell hypertrophy and enhanced SERCA2a and phosphorylated phospholamban (PLN) expression in H9C2 cells. Triamterene inhibited these effects at an effective dose to block TGR5. However, LCA failed to modify the free radical elevation induced by high-glucose in the H9c2 cells. Moreover, PKA inhibitors, but not an Epac blocker, markedly improved hyperglycemia-induced hypertrophy and attenuated the increased SERCA2a expression by LCA; it also attenuated the phosphorylated PLN and SERCA2a protein expression levels in high glucose-treated H9C2 cells. In conclusion, TGR5 activation stimulated protein kinase A (PKA) to enhance PLN phosphorylation, which activated SERCA2a to remove Ca from cytosol to sarcoplasmic reticulum in addition to the reduction of calcineurin/NFAT pathway signaling to ameliorate the hyperglycemia-induced cardiac hypertrophy shown in cardiomyocytes. TGR5 may service as a new target in the control of diabetic cardiomyopathy.
左心室肥厚是糖尿病患者的一个独立危险因素。TGR5 被证明在心脏中表达，但它在糖尿病诱导的心肌肥厚中的功能作用尚不清楚。本研究探讨了 TGR5 在高葡萄糖诱导的 H9C2 细胞肥大中的作用。在高浓度葡萄糖孵育后，H9C2 细胞表现出肥大反应。石胆酸（LCA）激活 TGR5 可改善细胞肥大，并增强 H9C2 细胞中 SERCA2a 和磷酸化磷蛋白（PLN）的表达。阿米洛利以有效剂量抑制这些作用以阻断 TGR5。然而，LCA 未能修饰高葡萄糖引起的 H9c2 细胞中自由基升高。此外，PKA 抑制剂，但不是 Epac 阻断剂，显著改善高血糖诱导的肥大，并减弱 LCA 引起的 SERCA2a 表达增加；它还减弱了高葡萄糖处理的 H9C2 细胞中磷酸化 PLN 和 SERCA2a 蛋白表达水平。总之，TGR5 激活刺激蛋白激酶 A（PKA）增强 PLN 磷酸化，从而激活 SERCA2a 将 Ca 从细胞质转运到肌浆网，除了减少钙调神经磷酸酶/NFAT 信号通路来改善心肌细胞中高血糖诱导的心肌肥厚。TGR5 可能成为控制糖尿病心肌病的新靶点。
