title: 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 ofApoe-/-mice (Irs1/Apoe-/-) increased insulin signaling and function in the aorta. Atherosclerosis was significantly reduced inIrs1/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 ofAki/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 ofLdlr-/-andIrs1/Ldlr-/-mice decreased NO production and accelerated atherosclerosis, compared withLdlr-/-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.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Pingnian
authors.initials: P
authors.lastname: He
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Katagiri
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: I-Hsien
authors.initials: IH
authors.lastname: Wu
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mogher
authors.initials: M
authors.lastname: Khamaisi
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
authors.forename: Simone Rordam
authors.initials: SR
authors.lastname: Preil
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Maddaloni
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, University of Southern Denmark, Odense, Denmark; Danish Diabetes Academy, Odense, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Sørensen
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
authors.forename: Lars Melholt
authors.initials: LM
authors.lastname: Rasmussen
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.affiliation: Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: King