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.

Response by Viswambharan and Kearney to Letter Regarding Article, “Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop”

“…The discrepancy between our findings in hIRECO mice crossed with mice deficient in ApoE, which develop accelerated atherosclerosis, and those from ApoE null mice with overexpression of insulin receptor substrate-1 in endothelial cells, 4 which manifest blunted atherosclerosis, is intriguing. This may be linked to the specific signaling node at which insulin signaling is enhanced or indeed, as suggested by Rask-Madsen et al the activation of other downstream molecules.…”

“…1 Rask-Madsen et al have made a major and sustained contribution to contemporary understanding of insulin signaling in endothelial cells. [2][3][4] In the case of the seminal report of King et al 5,6 describing intracellular selectivity of insulin resistance in endothelial cells from obese rodents, they without doubt changed the way we think about insulin signaling in the endothelium in obesity and type 2 diabetes mellitus.…”

“…[2][3][4] In the case of the seminal report of King et al 5,6 describing intracellular selectivity of insulin resistance in endothelial cells from obese rodents, they without doubt changed the way we think about insulin signaling in the endothelium in obesity and type 2 diabetes mellitus.We generated hIRECO mice specifically to examine the effect of long-term enhancement of insulin sensitivity in the endothelium at the most proximal node in the insulin signaling pathway on the bioavailability of nitric oxide and progression of atherosclerosis. The rationale for this was underpinned by the following: (1) in a study of obese mice, we demonstrated that insulin sensitivity in the vasculature and tissues responsible for glucose uptake becomes temporospatially uncoupled 7 with hyperinsulinemic metabolic insulin resistance preceding insulin resistance in the endothelium, meaning that the insulin sensitive vasculature is exposed to excessive insulin stimulation in the early stages of obesity/type 2 diabetes mellitus.…”

Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKCδ Isoform Activation

“…The severity of atherosclerosis in MPKCδKO/ApoE −/− mice on HFD was studied since HFD with 60% of calories from fat, unlike AD, induces obesity, insulin resistance, and hyperglycemia in addition to hyperlipidemia 20 . The body weight of MPKCδKO/ApoE −/− mice and ApoE −/− mice were similar either on NC or HFD for 16 weeks (Supplemental Figure XIIIA), although HFD increased body weight significantly in both types of mice compared to NC.…”

Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance

“…Mice with endothelial-specific overexpression of IRS1 (ECIRS1 TG) with VE-cadherin promoter were described previously (28) (Supplementary Fig. 1 A ).…”