Cardiac TGR5 expression enhanced by hyperglycaemia in diabetic rats: A preclinical warning for disorders with excess bile acids

Abstract

Background: Diabetes is a risk factor for cardiovascular disorders. TGR5 levels are increased in cardiomyocytes exposed to hyperglycaemia. The objective of this study was to investigate the potential mechanism(s) for the increase in TGR5 levels in the hearts of diabetic rats. Materials and methods:We used streptozotocin -induced diabetic rats (STZ rats) to assess the role of hyperglycaemia in increased cardiac TGR5 levels. The expression levels of TGR5 and signal transducer and activator of transcription 3, both its phosphorylated form (p-STAT3) and its native form (STAT3), in heart tissues were measured using Western blots. Results:The increased levels of TGR5 and the ratio of p-STAT3 to STAT3 in cardiac tissues exposed to hyperglycaemic conditions were reversed by treating the hyperglycaemia. Additionally, the potential mechanisms of this effect were confirmed in a cultured rat cardiac cell line (H9c2) incubated in high-glucose (HG) medium to mimic the changes observed in vivo. TGR5 expression increased in parallel with the increased ratio of p-STAT3 and STAT3 in H9c2 cells exposed to HG, and these effects were reversed by treatment with stattic at a dose sufficient to inhibit STAT3. Similarly, the antioxidant tiron also produced the same effects in H9c2 cells. Conclusion:Increased cardiac TGR5 levels in a type-1 diabetes model were related to hyperglycaemia, which produces free radicals to activate STAT3 for the higher expression of TGR5 in the heart. Therefore, an elevation in circulating bile acids from hepatic disorders and/or others shall be handled carefully in diabetic patients.

TGR5 Expression Is Associated with Changes in the Heart and Urinary Bladder of Rats with Metabolic Syndrome

“…In the present study, TGR5 expression in the heart or urinary bladder was noted to be increased in HFD-fed rats. This finding is consistent with the hyperglycemia-induced changes in the hearts of diabetic rats [9]. Insulin resistance is exacerbated by an increase in inflammation, along with a parallel increase in the activation of TGR5 [35], which may play a protective role in obese rats.…”

“…Insulin resistance is exacerbated by an increase in inflammation, along with a parallel increase in the activation of TGR5 [35], which may play a protective role in obese rats. TGR5 was identified in vivo, which may be targeted by bile acids [5] in both the healthy and diseased states [9]. TGR5 activation is beneficial to cardiac function [8] and MetS.…”

“…Therefore, TGR5 activation is introduced to provide benefits to cardiac function [8]. Recently, it has been documented that cardiac TGR5 expression is promoted in type-1 diabetic rats [9], mainly due to hyperglycemia, which seems to Life 2021, 11, 695 2 of 14 be related to compensatory homeostasis. However, TGR5 expression in other metabolic disorders remains unknown.…”