Dopamine 1 receptors inhibit apoptosis via activating CSE/H2S pathway in high glucose‐induced vascular endothelial cells.

High glucose (HG)‐induced dysfunction of vascular endothelial cells plays a crucial role in the development of diabetic vascular complications. Inhibition of cystathionine γ‐synthase/hydrogen sulfide (CSE/H2S) pathway is one of the causes of vascular endothelial cell injury induced by HG. Dopamine D1 receptors (DR1) are widely expressed and regulate important physiological functions in the vascular system. However, the effect of DR1 inhibition on HG‐induced vascular endothelial apoptosis by regulating the CSE/H2S pathway is unclear. Therefore, we aimed to determine if DR1 can regulate the CSE/H2S pathway and regulate the effect of DR1 on HG‐induced apoptosis in human umbilical vein endothelial cells. In this study, we found that HG treatment significantly decreased the expression of DR1 and CSE and the endogenous content of H2S; DR1 agonist SKF 38393 reversed these effects, while sodium hydrosulfide (NaHS) only increased CSE expression and the endogenous H2S production and had no effect on DR1 expression. Meanwhile, HG significantly increased the intracellular calcium concentration ([Ca2+]i), and SKF 38393 further increased HG‐induced [Ca2+]i. In addition, HG increased the lactate dehydrogenase activity, malondialdehyde and reactive oxygen species contents, apoptotic rate, the expression of cleaved caspase‐3, caspase‐9, and cytochrome c, and the activity of phosphorylated‐inhibitor of nuclear factor‐kappaBα (NF‐κBα) (p‐IκBα) and phosphorylated‐NF‐κB (p‐NF‐κB), and reduced cell viability, superoxide dismutase activity, and Bcl‐2 expressions. SKF 38393 and NaHS markedly reversed the effect of HG. The effect of SKF 38393 was similar to N‐acetyl‐ l‐cysteine (an inhibitor of oxidative stress) or pyrrolidinedithiocarbamate ammonium (an NF‐kB inhibitor). Taken together, DR1 upregulates the CSE/H2S pathway by increasing the [Ca2+]i, which inhibits HG‐induced apoptosis via downregulating NF‐κB/IκBα pathway in vascular endothelial cells. [ABSTRACT FROM AUTHOR]