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 9

Effect of endothelial EDNRB signaling on atherosclerosis in Ldlr–/– mice.

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Effect of endothelial EDNRB signaling on atherosclerosis in Ldlr–/– mice...
(A) IB of EDNRB protein levels in EC from Ldlr–/– (n = 6), Ednrb–/–/Ldlr–/– (n = 6), and Irs1/Ednrb–/–/Ldlr–/– mice (n = 6). EDNRB and p-Akt expression were separately blotted in different gels. (B) Representative en face staining and (C) quantification of lesion area in aortas in Ldlr–/– (n = 6), Ednrb–/–/Ldlr–/– (n = 6), and Irs1/Ednrb–/–/Ldlr–/– (n = 6) mice 16 weeks after HFD (n = 6). Original magnification, ×2. (D) Histological analysis and (E) quantification of cross sections from the aortic sinus stained with trichrome and immunostained with anti-MAC2. Original magnification, ×4; scale bar: 100 μm. (F) IB of EDNRB in aortas from Ldlr–/– (n = 6), Ednrb–/–/Ldlr–/– (n = 6), and Irs1/Ednrb–/–/Ldlr–/– (n = 6) mice fed HFD for 16 weeks. (G) Schematic mechanism of increased NO production in EC from Irs1/Apoe–/– mice. Data are represented as mean ± SEM of at least 6 mouse replicates. P < 0.05, P < 0.01 (1-way ANOVA for multiple comparisons involving 1 factorial variable and 2-tailed Student’s t test for pairwise comparisons).