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.
Highlights
Type 2 diabetes mellitus (T2DM) is a major health concern and burden on economies, which affected 2.8% of the world population in 2000 with morbidity estimated to reach 4.4% by 2030 [1]
Reactive oxygen species (ROS) elevation, inflammation, and apoptosis, which are caused by high blood glucose, are major precursors and contributors to the development of diabetic cardiomyopathy [7,8,9]
The protein expression of pIκBα and NF-κB was increased up to 6 and 2 h, respectively, and decreased thereafter (Figure 1(b)). These data indicated that HG may induce the inflammatory response through activation of NF-κB signaling in mouse cardiomyocytes
Summary
Type 2 diabetes mellitus (T2DM) is a major health concern and burden on economies, which affected 2.8% of the world population in 2000 with morbidity estimated to reach 4.4% by 2030 [1]. The cardiovascular complications are wide-ranging and due at least in part to chronic elevation of blood glucose levels. Reactive oxygen species (ROS) elevation, inflammation, and apoptosis, which are caused by high blood glucose, are major precursors and contributors to the development of diabetic cardiomyopathy [7,8,9]. Such pathological changes induce diastolic function impairments, myocardial fibrosis, and cardiac complications [3, 6, 8, 9]
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