Abstract
Endothelial cell dysfunction is one of the main reasons for type II diabetes vascular complications. Hydrogen sulphide (H2S) has antioxidative effect, but its regulation on mitochondrial dynamics and mitophagy in aortic endothelial cells under hyperglycaemia and hyperlipidaemia is unclear. Rat aortic endothelial cells (RAECs) were treated with 40 mM glucose and 200 μM palmitate to imitate endothelium under hyperglycaemia and hyperlipidaemia, and 100 μM NaHS was used as an exogenous H2S donor. Firstly, we demonstrated that high glucose and palmitate decreased H2S production and CSE expression in RAECs. Then, the antioxidative effect of H2S was proved in RAECs under high glucose and palmitate to reduce mitochondrial ROS level. We also showed that exogenous H2S inhibited mitochondrial apoptosis in RAECs under high glucose and palmitate. Using Mito Tracker and transmission electron microscopy assay, we revealed that exogenous H2S decreased mitochondrial fragments and significantly reduced the expression of p‐Drp‐1/Drp‐1 and Fis1 compared to high‐glucose and high‐palmitate group, whereas it increased mitophagy by transmission electron microscopy assay. We demonstrated that exogenous H2S facilitated Parkin recruited by PINK1 by immunoprecipitation and immunostaining assays and then ubiquitylated mitofusin 2 (Mfn2), which illuminated the mechanism of exogenous H2S on mitophagy. Parkin siRNA suppressed the expression of Mfn2, Nix and LC3B, which revealed that it eliminated mitophagy. In summary, exogenous H2S could protect RAECs against apoptosis under high glucose and palmitate by suppressing oxidative stress, decreasing mitochondrial fragments and promoting mitophagy. Based on these results, we proposed a new mechanism of H2S on protecting endothelium, which might provide a new strategy for type II diabetes vascular complication.
Highlights
Diabetes mellitus is firmly established as a major threat to human health due to its severe complications in the cardiovascular system [1]
Accumulating evidence indicates that hyperglycaemia and hyperlipidaemia induced by type II diabetes could increase the production of ROS, increasing cell surface adhesion molecule expression and inflammatory changes that contribute to micro- and macrovascular damages [3]
The H2S production of Rat aortic endothelial cells (RAECs) was impaired by high glucose (HG)+Pal, which suggested that H2S might participate in endothelial cell injuries induced by hyperglycaemia and hyperlipidaemia
Summary
Diabetes mellitus is firmly established as a major threat to human health due to its severe complications in the cardiovascular system [1]. Endothelial cell dysfunctions (ECD) play an important role in diabetic cardiovascular complications, which can result in the impairment of vasodilation, impairment of angiogenic properties and promotion of thrombus formation [2]. Accumulating evidence indicates that hyperglycaemia and hyperlipidaemia induced by type II diabetes could increase the production of ROS, increasing cell surface adhesion molecule expression and inflammatory changes that contribute to micro- and macrovascular damages [3]. Mitochondria are morphologically dynamic organelles, undergoing constant fission and fusion events. Some studies demonstrated that the change in mitochondrial morphology was closely associated with the occurrence of mitophagy, which maintained mitochondrial homoeostasis [5, 6].
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