Hydrogen Sulfide Plays an Important Role in Diabetic Cardiomyopathy

Figures

• 

  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 KATP 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).