Amelioration of Endothelial Dysfunction in Diabetes: Role of Takeda G Protein–Coupled Receptor 5

Abstract

Diabetes mellitus (DM) eventually leads to chronic vascular complications, resulting in cardiovascular diseases. DM-associated endothelial dysfunction (ED) plays an important role in the development of chronic vascular complications. Low endothelial nitric oxide synthase (eNOS) activity, inflammation, and oxidative stress all contribute to ED. The G protein–coupled receptor Takeda G protein–coupled receptor 5 (TGR5) is a membrane receptor for bile acids that plays an important role in the regulation of glucose metabolism. Recent studies have shown that TGR5 is involved in the regulation of various mediators of ED, which suggests that TGR5 may represent a target for the treatment of DM-associated ED. In this review, we summarize the principal mechanisms of DM-associated ED, then propose TGR5 as a novel therapeutic target on the basis of its mechanistic involvement, and suggest potential directions for future research.

Neuroprotective Panel of Olive Polyphenols: Mechanisms of Action, Anti-Demyelination, and Anti-Stroke Properties

“…Polyphenols from olive oil and leaves are thought to inhibit mitochondrion ROS and are therefore valuable agents in diabetes therapy [ 151 ]. Endothelial dysfunction is primarily responsible for impaired vasorelaxation and vasodilator factor production in diabetes, but it is closely followed by the development of vascular smooth muscle cell dysfunction [ 152 , 153 ]. The improvement in hyperglycemia with concomitant consumption of olive polyphenols can restore endothelium-dependent vasodilation in experimental models of diabetes [ 152 ].…”

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Role of Takeda G protein‑coupled receptor 5 in microvascular endothelial cell dysfunction in diabetic retinopathy (Review)

“…Previous studies have shown that activation of TGR5 can effectively increase eNOS expression; and its expression level is increased through the bile salt-TGR5-cAMP pathway and the TGR5-GLP-1-PI3K-eNOS pathway. ( 17 , 27 ). In addition, a study has also shown that taurolithocholic acids (TLCAs), taurocholic acid (TCA), and taurochenodeoxycholic acid (TCDCA) as agonists of eNOS has been shown to elevate eNOS expression and Ser1177 phosphorylation of this enzyme, leading to increased nitric oxide (NO) production ( 96 ).…”

“…ED occurs when ECs are unable to maintain homeostasis of the vascular environment. It is a systemic pathological condition characterized by changes in the phenotype of ECs, which leads to diminished vasoconstriction and the formation of a proinflammatory and prothrombotic state ( 27 ). ED forms the basis of the chronic microvascular and macrovascular complications of diabetes.…”