Hydrogen Sulfide Plays an Important Role in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy is an important complication of diabetes mellitus and the main cause of diabetes death. Diabetic cardiomyopathy is related with many factors, such as hyperglycemia, lipid accumulation, oxidative stress, myocarditis, and apoptosis. Hydrogen sulfide (H₂S) is a newly discovered signal molecule, which plays an important role in many physiological and pathological processes. Recent studies have shown that H₂S is involved in improving diabetic cardiomyopathy, but its mechanism has not been fully elucidated. This review summarizes the research on the roles and mechanisms of H₂S in diabetic cardiomyopathy in recent years to provide the basis for in-depth research in the future.

Keywords: cardiovascular diseases; diabetic; diabetic cardiomyopathy; diabetic vascular diseases; hydrogen sulfide.

Figure 1

In vivo synthesis process and biological function of hydrogen sulfide (H₂S). In the process of endogenous H₂S production, firstly, cystathionine-β-synthase (CBS) catalyzes the β-substitution reaction of homocysteine with serine to produce L-cystathionine. L-cystenine is produced by the elimination of α, γ-cysteine of L-cystathionine catalyzed by cystathionine-γ-lyase (CSE). L-cystenine then produces hydrogen sulfide (H₂S) via β elimination reaction catalyzed by CSE/CBS. L-cystenine also produces 3-mercaptopyruvate (3-MP) by transferring its amines to α-ketoglutarate catalyzed by cysteine aminotransferase (CAT). 3-Mercaptopyruvate thiotransferase (3-MST) catalyzes the sulfur of 3-MP to convert into H₂S. In cardiomyocytes that mainly express CSE, H₂S is produced with L-cysteine as substrate under the catalysis of CSE. (The part in the figure is marked in red.) H₂S plays important roles in many physiological processes, including vasodilation, blood pressure reduction, anti-apoptosis, anti-inflammation, anti-oxidative stress, cell survival/death, cell differentiation, cell proliferation/hypertrophy, mitochondrial bioenergetics/biogenesis, and endoplasmic reticulum stress.

Figure 2

Schematic diagram of the mechanism of exogenous H₂S improving diabetic cardiomyopathy (DCM). Exogenous H₂S improves DCM by suppressing oxidative stress, inflammation, and apoptosis. Exogenous H₂S improves DCM by inhibiting apoptosis through suppressing endoplasmic reticulum stress (ERS) or inhibiting reactive oxygen species (ROS)/ERS–mediated apoptosis through suppressing Mfn-2 expression. Exogenous H₂S improves DCM by suppressing ubiquitylation of kelch-like ECH related protein 1 (Keap-1) to promote autophagy for ubiquitin clearance. Exogenous H₂S improves DCM by improving cardiac mitochondrial function through activating sirtuin 3 (SIRT3). Exogenous H₂S could improve DCM by activating K_ATP channels.

Figure 3

CSE-derived H₂S mediates the moxonidine improvements of DCM. Diabetic state can inhibit the CSE/H₂S system, and moxonidine can activate myocardial imidazoline I1 receptor to improve DCM by promoting the CSE/H₂S system to increase endogenous H₂S production or by promoting the CSE/H₂S system to inhibit death related protein kinase 3 (DAPK-3).