DCA-TGR5 signaling activation alleviates inflammatory response and improves cardiac function in myocardial infarction

• Published in: Journal of molecular and cellular cardiology Vol. 151; pp. 3 - 14
• Main Authors: Wang, Jiaxing, Zhang, Jianshu, Lin, Xianjuan, Wang, Yupeng, Wu, Xiang, Yang, Fan, Gao, Wei, Zhang, Yan, Sun, Jinpeng, Jiang, Changtao, Xu, Ming
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2021
• Subjects: Animals; Anti-Inflammatory Agents - metabolism; Cell Hypoxia; DCA; Deoxycholic Acid - blood; Deoxycholic Acid - metabolism; Fibroblasts - metabolism; Humans; Inflammation; Inflammation - blood; Inflammation - metabolism; Male; Mice; Mice, Inbred C57BL; Myocardial infarction; Myocardial Infarction - blood; Myocardial Infarction - physiopathology; Myocardial Ischemia - blood; Myocardial Ischemia - pathology; Myocardial Ischemia - physiopathology; Myocytes, Cardiac - metabolism; Reactive Oxygen Species - metabolism; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; TGR5; Myocardial infarction; TGR5; Inflammation; DCA
• ISSN: 0022-2828; 1095-8584; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.10.014

The progression of myocardial infarction (MI) involves multiple metabolic disorders. Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate multiple cardiovascular functions. G protein-coupled bile acid receptor (TGR5) is one of the receptors sensing bile acids to mediate their biological functions. In this study, we aimed to elucidate the effects of bile acids-TGR5 signaling pathways in myocardial infarction (MI). Blood samples of AMI patients or control subjects were collected and plasma was used for bile acid metabolism analysis. We discovered that bile acid levels were altered and deoxycholic acid (DCA) was substantially reduced in the plasma of AMI patients. Mice underwent either the LAD ligation model of MI or sham operation. Both MI and sham mice were gavaged with 10 mg/kg/d DCA or vehicle control since 3-day before the operation. Cardiac function was assessed by ultrasound echocardiography, infarct area was evaluated by TTC staining and Masson trichrome staining. Administration of DCA improved cardiac function and reduced ischemic injury at the 7th-day post-MI. The effects of DCA were dependent on binding to its receptor TGR5. Tgr5−/− mice underwent the same MI model. Cardiac function deteriorated and infarct size was increased at the 7th-day post-MI, which were not savaged by DCA administration. Moreover, DCA inhibited interleukin (IL)-1β expression in the infarcted hearts, and ameliorated IL-1β activation at 1-day post-MI. DCA inhibited NF-κB signaling and further IL-1β expression in cultured neonatal mouse cardiomyocytes under hypoxia as well as cardio-fibroblasts with the treatment of LPS. DCA-TGR5 signaling pathway activation decreases inflammation and ameliorates heart function post-infarction. Strategies that control bile acid metabolism and TGR5 signaling to ameliorate the inflammatory responses may provide beneficial effects in patients with myocardial infarction. [Display omitted] •Deoxycholic acid (DCA) was decreased in the plasma of MI patients.•Administration of DCA improved MI injury in mice.•DCA-TGR5 signaling inhibited IL-1β inflammatory activation in the heart post-MI.•DCA-TGR5 signaling activation inhibited hypoxia-induced ROS production in cardiomyocytes.