Overexpression of TGR5 alleviates myocardial ischemia/reperfusion injury via AKT/GSK-3β mediated inflammation and mitochondrial pathway

Abstract

Ischemia/reperfusion (I/R) injury reduces cell proliferation, triggers inflammation, promotes cell apoptosis and necrosis, which are the leading reasons of morbidity and mortality in patients with cardiac disease. TGR5 is shown to express in hearts, but its functional role in I/R-induced myocardial injury is unclear. In the present study, we aimed to explore the underlying molecular mechanism of TGR5 in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury in vitro. The results showed that TGR5 was significantly up-regulated in H9C2 (rat cardiomyocyte cells) and human cardiomyocytes (HCMs) after H/R. Overexpression of TGR5 significantly improved cell proliferation, alleviated apoptosis rate, the activities of caspase-3, cleaved caspases-3 and Bax protein expression levels, and increased Bcl-2 level. Overexpression of TGR5 significantly up-regulated ROS generation, stabilized the mitochondrial membrane potential (MMP), and reduced the concentration of intracellular Ca2+ as well as cytosolic translocation of mitochondrial cytochrome c (cyto-c). Meanwhile, overexpressed TGR5 also enhanced the mRNA and protein levels of interleukin (IL)-10, and decreased the mRNA and protein levels of IL-6 and tumor necrosis factor α (TNF-α). The shTGR5+H/R group followed opposite trends. In addition, overexpressed TGR5 induced an increase in the levels of p-AKT and p-GSK-3β. The protective effects of TGR5 were partially reversed by AKT inhibitor MK-2206. Taken together, these results suggest that TGR5 attenuates I/R-induced mitochondrial dysfunction and cell apoptosis as well as inflammation, and these protections may through AKT/GSK-3β pathway.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

“…TGR5, as a bile acid receptor, has been shown roles in alleviating the liver ischemia/reperfusion-related inflammation and protecting hepatocytes from ischemia/reperfusion-related apoptosis [ 29 ]. Overexpression of TGR5 significantly improved cardiomyocyte cell proliferation, alleviated apoptosis rate [ 30 ]. INT-777, a specific TGR5 agonist, alleviates Aβ1–42-induced neuronal apoptosis in the hippocampus and frontal cortex [ 13 ].…”

Restoration of NRF2 attenuates myocardial ischemia reperfusion injury through mediating microRNA‐29a‐3p/CCNT2 axis

“…One-way analysis of variance (ANOVA) was adopted for comparisons among multiple groups while Tukey's method for pairwise comparisons Generated with reduced proliferation and enhanced inflammation, apoptosis and necrosis, MI/RI imposes a great threat on patients with cardiac diseases with high morbidity and mortality. 24 Given that, this study is launched to uncloak the mystery of MI/RI from the perspective of NRF2/miR-29a-3p/CCNT2 axis and the mainstay of this study elucidated that upregulation of NRF2 or miR-29a-3p attenuated MI/RI through down-regulating CCNT2. (F) Dual-luciferase reporter gene assay to verify the interaction between miR-29a-3p and CCNT2; *p < 0.05 compared with the control group; #p < 0.05 compared with the Oe-NC group;^p < 0.05 compared with the mimic NC group; &p < 0.05 compared with the miR-29a-3p mimic group; N= 3.…”

Anti-Myocardial Ischemia Reperfusion Injury Mechanism of Dried Ginger-Aconite Decoction Based on Network Pharmacology

“…Some studies indicate that 18 million people die of cardiovascular diseases every year globally, of which MI/RI incidence accounts for around 50% (Wei, 2017). MI/RI pathogenesis involves the interaction of multiple mechanisms, including vasoconstrictor release, non-reperfusion, deep inflammatory response, apoptosis and necrosis (Chen et al, 2020;Li et al, 2020a;Samiotis et al, 2021). Albeit not quite effective, the current treatment methods for MI/RI are percutaneous coronary intervention and the use of related thrombolytic drugs; nevertheless, MI/RI still has a high mortality rate worldwide.…”