Insulin decreases atherosclerosis by inducing endothelin receptor B expression
Kyoungmin Park, Akira Mima, Qian Li, Christian Rask-Madsen, Pingnian He, Koji Mizutani, Sayaka Katagiri, Yasutaka Maeda, I-Hsien Wu, Mogher Khamaisi, Simone Rordam Preil, Ernesto Maddaloni, Ditte Sørensen, Lars Melholt Rasmussen, Paul L. Huang, George L. King
Kyoungmin Park, Akira Mima, Qian Li, Christian Rask-Madsen, Pingnian He, Koji Mizutani, Sayaka Katagiri, Yasutaka Maeda, I-Hsien Wu, Mogher Khamaisi, Simone Rordam Preil, Ernesto Maddaloni, Ditte Sørensen, Lars Melholt Rasmussen, Paul L. Huang, George L. King
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Research Article Vascular biology

Insulin decreases atherosclerosis by inducing endothelin receptor B expression

Abstract

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.

Authors

Kyoungmin Park, Akira Mima, Qian Li, Christian Rask-Madsen, Pingnian He, Koji Mizutani, Sayaka Katagiri, Yasutaka Maeda, I-Hsien Wu, Mogher Khamaisi, Simone Rordam Preil, Ernesto Maddaloni, Ditte Sørensen, Lars Melholt Rasmussen, Paul L. Huang, George L. King

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Figure 6

NO production in EC from Irs1/Apoe–/– mice and its relationship to EDN1 and EDNRB.

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NO production in EC from Irs1/Apoe–/– mice and its relationship to EDN1 ...
(A) EDN1-induced NO production in the aortic EC from Irs1/Apoe–/– and Apoe–/– mice. NO production was visualized by DAF-2DA fluorescence intensity (FI) and quantified. Original magnification, ×15; scale bar: 5 μm. (B) EDN1-induced NO production in insulin-stimulated aortic EC from Apoe–/– and Irs1/Apoe–/– mice pretreated with BQ-788 (0.1 mM) or L-NAME (0.5 mM). NO production was visualized by DAF-2DA and quantified. Original magnification, ×20; scale bar: 5 μm. (C) Nω-nitro-L-arginine–sensitive accumulation of cGMP in VSMC from Apoe–/– and Irs1/Apoe–/– mice stimulated with EDN1 pretreated with BQ-788 or L-NAME. (D) Accumulation of cGMP in aortas from WD- or HFD-fed Apoe–/– and Irs1/Apoe–/– mice. (E and F) Ca2+ accumulation was visualized and quantified by Fluor-4 in EC. Original magnification, ×15; scale scale bar: 5 μm. Data are represented as mean ± SEM of at least 5 cellular replicates for NO production experiments in EC and cGMP experiments in VSMC. **P < 0.01 (3-way ANOVA for multiple comparisons involving 3 factorial variables and 2-tailed Student’s t test for pairwise comparisons).