Insulin decreases atherosclerosis by inducing endothelin receptor B expression

Area of Science:

• Cardiovascular Biology
• Metabolic Diseases
• Endothelial Function

Background:

• Diabetes-induced endothelial cell (EC) insulin resistance and dysfunction accelerate atherosclerosis.
• The specific role of enhancing EC-targeted insulin action in mitigating diabetes-related atherosclerosis remains unclear.

Purpose of the Study:

• To investigate whether overexpressing insulin receptor substrate-1 (IRS1) in ECs can reduce atherosclerosis in diabetic conditions.
• To elucidate the underlying mechanisms of insulin's antiatherogenic effects in ECs, focusing on nitric oxide (NO) and endothelin receptor B (EDNRB) pathways.

Main Methods:

• Overexpression of IRS1 in the endothelium of Apoe-/- mice (Irs1/Apoe-/-) and Aki/Apoe-/- mice.
• Induction of diet-related hyperinsulinemia and hyperglycemia.
• Assessment of atherosclerosis progression, insulin signaling, NO production, and EDNRB expression.
• Genetic deletion of eNOS (AKI) and EDNRB in ECs of relevant mouse models (Ldlr-/-, Irs1/Ldlr).

Main Results:

• IRS1 overexpression in ECs of Irs1/Apoe-/- mice significantly reduced atherosclerosis under diabetic conditions.
• Insulin's antiatherogenic effect was mediated by increased NO action, EDNRB expression, and intracellular calcium.
• IRS1 overexpression in Aki/Apoe-/- mice also decreased atherosclerosis, indicating insulin's action independent of the canonical eNOS Ser1176 phosphorylation site.
• Endothelial EDNRB expression was reduced in diabetic patients and rodents but upregulated by insulin via the P13K/Akt pathway.
• EDNRB deletion in ECs accelerated atherosclerosis in Ldlr-/- and Irs1/Ldlr mice.

Conclusions:

• Accelerated atherosclerosis in diabetes can be mitigated by enhancing EC insulin signaling specifically through IRS1/Akt.
• This improvement is achieved by inducing EDNRB expression and subsequent NO production, highlighting a novel therapeutic target.