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Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Year: 2018
Type: article
Abstract: Insulin resistance in endothelial cells contributes to the development of cardiovascular disease in patients with type 2 diabetes. Acid sphingomyelinase (ASM) is a soluble glycoprotein which plays a vital role in the development and progression of various diseases such as cardiovascular and metabolic diseases. However, it remains unknown ifASMregulates insulin resistance in vascular endothelial cells in type 2 diabetes.ASMdown‐regulation with gene silencing and selective inhibitor amitriptyline was used in the rat aortic endothelial cells (RAECs) treated with palmitic acid (PA), a common saturated free fatty acid, which is thought to be the major cause of insulin resistance. It was shown thatASMdown‐regulation increased glucose uptake and glucose transporter‐4 (Glut4) expression and reversed the phosphorylation ofpIRS‐1‐ser307 andAKT‐ser473 via ceramide, consequently resulting in the decrease of the production of endothelial nitric oxide synthase (eNOS) and nitric oxide inPA‐inducedRAECs. We further found thatASMdown‐regulation blocked the Nox2‐ and Nox4‐dependent superoxide (O2−·) generation, which regulated glucose metabolism inRAECs duringPAstimulation.In vivo, amitriptyline relieved the vasodilatory response to acetylcholine and restored the level of ceramide, Nox2 and Nox4 in the aorta endothelium of high‐fat diet‐fed rats following an injection of streptozotocin. Taken together, these results suggest thatASMdown‐regulation can improve endothelial insulin resistance which is attributed to inhibiting redox signalling inRAECs. Thus, these data support the idea thatASMis a promising clinical biomarker and potential therapeutic target for diabetic vascular complication.
DOI: 10.1111/bcpt.13073
Language: English
Open Access status: bronze
OpenAlex ID: W2809475309
FWCI: 0.628
Cites: 42
Cited by: 19
Related to: 10