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 7

Characterization of NO production in EC from Irs1/Aki/Apoe–/– mice with mutated eNOS Ser to Ala at 1176 (AKI).

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Characterization of NO production in EC from Irs1/Aki/Apoe–/– mice with ...
(A) IB and densitometry of p-eNOS in aortas of Apoe–/–, Aki/Apoe–/–, and Irs1/Aki/Apoe–/– mice. (B and C) En face staining and quantification of aortas from Apoe–/– (n = 5), Aki/Apoe–/– (n = 7), and Irs1/Aki/Apoe–/– (n = 8) mice fed on HFD. (D) Representative example (upper) and quantification (lower) of cross-sections from the aortic sinus stained with GALECTIN-3. A higher magnification (×4) and scale bar: 100 μm. Data are represented as mean ± SEM of at least 5 mouse replicates or least 5 cellular replicates for NO production experiments. P < 0.05, P < 0.01 (1-way/2-way ANOVA for multiple comparisons involving 1 or 2 factorial variables and 2-tailed Student’s t-test for pairwise comparisons).