Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress

Abstract

High glucose- (HG-) induced cardiomyocyte injury is the leading cause of diabetic cardiomyopathy, which is associated with the induction of inflammatory responses and oxidative stress. TGR5 plays an important role in the regulation of glucose metabolism. However, whether TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury is unknown. Neonatal mouse cardiomyocytes were isolated and incubated in a HG medium. Protein and mRNA expression was detected by western blotting and RT-PCR, respectively. Cell apoptosis was determined by Hoechst 33342 staining and flow cytometry. After treatment of cells with HG, TGR5-selective agonist INT-777 reduced the increase in expression of proinflammatory cytokines and NF-κB, whereas pretreatment of cells with TGR5 shRNA significantly reduced the inhibitory effects of INT-777. We also found that INT-777 increased the protein expression of Nrf2 and HO-1. In the presence of TGR5 shRNA, the expression of Nrf2 and HO-1 was reduced, indicating that TGR5 may exert an antioxidant effect partially through the Nrf2/HO-1 pathway. Furthermore, INT-777 treatment inhibited HG-induced ROS production and apoptosis that were attenuated in the presence of TGR5 shRNA or ZnPP (HO-1 inhibitor). Activation of TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury and could be a pharmacological target for the treatment of diabetic cardiomyopathy.

Melatonin Attenuates Diabetic Myocardial Microvascular Injury through Activating the AMPK/SIRT1 Signaling Pathway

“…Numerous evidences have indicated that oxidant stress plays an essential role in DM-associated cardiovascular complication progression and is often correlated with CMEC dysfunction [30]. Previous studies have been showed that hyperglycemia could induce oxidant stress injury in mammal cells, such as mouse microvascular endothelial cells [31], cardiomyocyte [32], and HK-2 cells [33]. Consistent with findings of these other studies, our results showed that hyperglycemia enhanced intracellular ROS and MDA production, and inhibited SOD activity in CMECs.…”

Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis, and Oxidative Stress

“…Under oxidative stress, Keap1 is inactivated, Nrf2 releases from Keap1 and translocates into the nucleus, where it triggers the expression of endogenous antioxidant/detoxifying proteins such as HO-1 and NQO-1. [38,39] Our www.advancedsciencenews.com www.mnf-journal.com results indicated that the expression levels of Nrf2 and its downstream factors HO-1 and NQO-1 were decreased and the level of Keap1 was increased in diabetic mice. Accordingly, the SYR treatment effectively up-regulated the expression of Nrf2, HO-1, and NQO-1 and down-regulated the expression of Keap1 in diabetic mice.…”

Irisin ameliorates high glucose‐induced cardiomyocytes injury via AMPK/mTOR signal pathway

“…Diabetic cardiomyopathy is a health‐threatening disease with myocardial damage (Dillmann, 2019). Hyperglycemia‐caused apoptosis, increased reactive oxygen species (ROS), and inflammation responses in cardiomyocytes (CMs) are the main mechanisms of diabetic cardiomyopathy (L. Deng et al, 2019; J. Y. Deng et al, 2019; Zhao, Liu, & Li, 2019; M. X. Zhao et al, 2017). The existing study has shown that the cellular and molecular mechanisms of heart injury caused by high glucose (HG) are complex and multifactorial (Wu et al, 2020).…”