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.

Keywords: TGR5; diabetes mellitus; endothelial dysfunction; endothelial nitric oxide synthase; inflammation; oxidative stress.

FIGURE 1

Mechanism of endothelial dysfunction associated with diabetes. In DM, cells exist in a high-glucose environment, but the etiology of ED associated with DM can be divided into two components: first, oxidative stress and inflammation; and second the uncoupling of eNOS and a reduction in NO production. The main mediators of oxidative stress and inflammation are ROS and NF-κB. The mechanism of eNOS decoupling involves (1) abnormal activation of eNOS, leading to a reduction in NO production; (2) inhibition of the PI3K/AKT/eNOS pathway as a component of insulin resistance; and (3) ROS activation, leading to a reduction in normal eNOS activation and an increase in the concentration of inhibitory BH2.

FIGURE 2

Mechanism whereby TGR5 protects against high-glucose-induced endothelial damage. (1) Negative effect (red line): inhibition of the generation of ROS and the activation of NF-κB, thereby reducing eNOS decoupling and NF-κB–mediated ED. (2) Positive effect (green line): increase in eNOS expression via the TGR5-GLP-1-PI3K-eNOS pathway, which mimics GLP-1 action.