Insulin decreases atherosclerosis by inducing endothelin receptor B expression
Kyoungmin Park, … , Paul L. Huang, George L. King
Kyoungmin Park, … , Paul L. Huang, George L. King
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e86574. https://doi.org/10.1172/jci.insight.86574.
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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 1

Effect of endothelial overexpression of IRS1 on vascular insulin sensitivity.

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Effect of endothelial overexpression of IRS1 on vascular insulin sensiti...
(A) Schematic representation of IRS1 Tg. IB of IRS1 expression levels in aorta and lung. (B) IRS1 mRNA levels in muscle and aorta. (C) IB and densitometry of p-Akt protein levels in EC after insulin stimulation. (D) IB of p-Akt levels in VSMC. (E and F) IB and densitometry of p-Akt and p-eNOS levels in EC. The IBs are representative of 3 separate experiments that gave similar results. (G and H) IB and densitometry of p-Akt and p-eNOS protein levels in aortas from Apoe–/– and Irs1/Apoe–/– mice treated with insulin. IBs are representative of 3 separate experiments that gave similar results. Data are represented as mean ± SEM of at least 3 separate experiments. **P < 0.01 (2-way ANOVA for multiple comparisons involving 2 factorial variables and 2-tailed Student’s t test for pairwise comparisons).