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首页> 外文期刊>Cardiovascular therapeutics >TGR TGR 5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure‐induced stress in mice
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TGR TGR 5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure‐induced stress in mice

机译：TGR TGR 5激活会诱导心脏的细胞保护变化，并改善对小鼠的生理，尿液和压力诱导的胁迫的心肌保护性能

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Abstract Introduction Administration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid ( INT ‐777), activates the membrane GPCR , TGR 5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR 5 agonists, and the role for TGR 5, on myocardial cell biology and stress response are unknown. Methods Mice were fed chow supplemented with 0.5% cholic acid ( CA ) or 0.025% INT ‐777, a specific TGR 5 agonist, or regular chow for 3?weeks. Anthropometric, biochemical, physiologic (electrocardiography and echocardiography), and molecular analysis was performed at baseline. CA and INT ‐777 fed mice were challenged with acute exercise‐induced stress, acute catecholamine‐induced stress, and hemodynamic stress induced by transverse aortic constriction ( TAC ) for a period of 8?weeks. In separate experiments, mice born with constitutive deletion of TGR 5 in cardiomyocytes ( CM ‐ TGR 5 del ) were exposed to exercise, inotropic, and TAC ‐induced stress. Results Administration of CA and INT ‐777 supplemented diets upregulated TGR 5 expression and activated Akt, PKA , and ERK 1/2 in the heart. CA and INT ‐777 fed mice showed improved exercise tolerance, improved sensitivity to catecholamine and attenuation in pathologic remodeling of the heart under hemodynamic stress. In contrast, CM ‐ TGR 5 del showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. Conclusions Bile acids, specifically TGR 5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR 5 plays a critical role in myocardial adaptability, and TGR 5 activation may represent a potentially attractive treatment option in heart failure.
机译：摘要胆酸施用，或其合成衍生物，6-α-乙基-33（S） - 甲基胆酸（int -777），激活膜GPCR，TGR 5，影响全身代谢，减少动脉粥样硬化，并有益于小鼠心血管生理学。 TGR 5激动剂的直接影响，以及TGR 5的作用，对心肌细胞生物学和应力反应是未知的。方法将小鼠补充有0.5％胆酸（CA）或0.025％嵌段-777，特异性TGR 5激动剂，或常规食物3〜3〜3周。基线进行人体计量，生化，生理（心电图和超声心动图）和分子分析。 CA和int -777美联储小鼠遭受急性运动诱导的应激，急性儿茶酚胺诱导的应激和横向性收缩（TAC）诱导的血流动力学应激，以80个星期。在单独的实验中，出生在心肌细胞（CM - TGR 5）中的Tgr 5的组成型缺失的小鼠暴露于运动，尿症和TAC屈服的应激。结果施用Ca和int -777补充饮食上调TGR 5表达和活化的Akt，PKA和心脏1/2。 CA和int -777美联储小鼠表现出改善的运动耐受性，改善了对儿茶酚胺的敏感性和血流动力学应力下心脏病理重塑的衰减。相比之下，CM - TGR 5 Del表现出对运动和儿茶酚胺挑战的反应差，以及血流动力学应激下加速心肌病的较高死亡率和迹象。结论胆汁酸，特异性Tgr 5激动剂，诱导心脏细胞保护变化，并改善小鼠对生理，肌室和血流动力学应激的心肌反应。 TGR 5在心肌适应性中起着关键作用，TGR 5激活可以代表心力衰竭中的潜在有吸引力的治疗选择。

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