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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 JCI+Insight ä ; 1 (6): ä Nephropedia Template TP
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Insulin decreases atherosclerosis by inducing endothelin receptor B expression #MMPMID27200419
Park K; Mima A; Li Q; Rask-Madsen C; He P; Mizutani K; Katagiri S; Maeda Y; Wu IH; Khamaisi M; Preil SR; Maddaloni E; Sørensen D; Rasmussen LM; Huang PL; King GL
JCI Insight ä[]; 1 (6): ä PMID27200419show ga
Endothelial cell (EC) insulin resistance and dysfunction, caused by diabetes, accelerates atherosclerosis. It is unknown whether specifically enhancing EC-targeted insulin action can decrease atherosclerosis in diabetes. Accordingly, overexpressing insulin receptor substrate-1 (IRS1) in the endothelia of Apoe?/? mice (Irs1/Apoe?/?) increased insulin signaling and function in the aorta. Atherosclerosis was significantly reduced in Irs1/ApoE?/? mice on diet-induced hyperinsulinemia and hyperglycemia. The mechanism of insulin?s enhanced antiatherogenic actions in EC was related to remarkable induction of NO action, which increases endothelin receptor B (EDNRB) expression and intracellular [Ca2+]. Using the mice with knockin mutation of eNOS, which had Ser1176 mutated to alanine (AKI), deleting the only known mechanism for insulin to activate eNOS/NO pathway, we observed that IRS1 overexpression in the endothelia of Aki/ApoE?/? mice significantly decreased atherosclerosis. Interestingly, endothelial EDNRB expression was selectively reduced in intima of arteries from diabetic patients and rodents. However, endothelial EDNRB expression was upregulated by insulin via P13K/Akt pathway. Finally EDNRB deletion in EC of Ldlr?/? and Irs1/Ldlr?/? mice decreased NO production and accelerated atherosclerosis, compared with Ldlr?/? mice. Accelerated atherosclerosis in diabetes may be reduced by improving insulin signaling selectively via IRS1/Akt in the EC by inducing EDNRB expression and NO production.