TY - JOUR
T1 - Insulin decreases atherosclerosis by inducing endothelin receptor B expression
AU - Park, Kyoungmin
AU - Mima, Akira
AU - Li, Qian
AU - Rask-Madsen, Christian
AU - He, Pingnian
AU - Mizutani, Koji
AU - Katagiri, Sayaka
AU - Maeda, Yasutaka
AU - Wu, I-Hsien
AU - Khamaisi, Mogher
AU - Preil, Simone Rordam
AU - Maddaloni, Ernesto
AU - Sørensen, Ditte
AU - Rasmussen, Lars Melholt
AU - Huang, Paul L
AU - King, George L
PY - 2016
Y1 - 2016
N2 - 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 [Ca(2+)]. 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.
AB - 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 [Ca(2+)]. 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.
KW - Journal Article
U2 - 10.1172/jci.insight.86574
DO - 10.1172/jci.insight.86574
M3 - Journal article
C2 - 27200419
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - e86574
ER -