title: Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1.
abstract: OBJECTIVE
  Prediabetic states are associated with accelerated atherosclerosis, but the availability of mouse models to study connections between these diseases has been limited. The aim of this study was to test the selective role of impaired insulin receptor/insulin receptor substrate-1 signaling on atherogenesis.
  
  
  RESULTS
  To address the effects of impaired insulin signaling associated with hyperinsulinemia on atherosclerosis in the absence of obesity and hyperglycemia, we generated insulin receptor (Insr)/insulin receptor substrate-1 (Insr1) double heterozygous apolipoprotein (Apoe)-knockout mice (Insr(+/-)Irs1(+/-)Apoe(-/-)) mice. Insr(+/-)Irs1(+/-)Apoe(-/-) mice fed a Western diet for 15 weeks showed elevated levels of fasting insulin compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. There were no significant differences in glucose, triglyceride, HDL, VLDL, cholesterol levels or free fatty acid in the plasma of Insr(+/-)Irs1(+/-)Apoe(-/-) and Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Atherosclerotic lesions were increased in male (brachiocephalic artery) and female (aortic tree) Insr(+/-)Irs1(+/-)Apoe(-/-) compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Bone marrow transfer experiments demonstrated that nonhematopoietic cells have to be Insr(+/-)Irs1(+/-) to accelerate atherosclerosis. Impaired insulin signaling resulted in decreased levels of vascular phospho-eNOS, attenuated endothelium-dependent vasorelaxation and elevated VCAM-1 expression in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice. In addition, phospho-ERK and vascular smooth muscle cell proliferation were significantly elevated in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice.
  
  
  CONCLUSIONS
  These results demonstrate that defective insulin signaling is involved in accelerated atherosclerosis in Insr(+/-)Irs1(+/-)Apoe(-/-) mice by promoting vascular dysfunction and inflammation.
authors.affiliation: Eastern Virginia Medical School, P.O. Box 1980, Norfolk, VA 23501, USA. galkinev@evms.edu
authors.forename: Elena V
authors.initials: EV
authors.lastname: Galkina
authors.forename: Matthew
authors.initials: M
authors.lastname: Butcher
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Keller
authors.forename: Matthew
authors.initials: M
authors.lastname: Goff
authors.forename: Anthony
authors.initials: A
authors.lastname: Bruce
authors.forename: Hong
authors.initials: H
authors.lastname: Pei
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Sarembock
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Nagelin
authors.forename: Suseela
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
authors.forename: Frank A
authors.initials: FA
authors.lastname: Lattanzio
authors.forename: Anca D
authors.initials: AD
authors.lastname: Dobrian
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006579:Heterozygote; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D055504:Insulin Receptor Substrate Proteins; D052250:Nitric Oxide Synthase Type III; D011972:Receptor, Insulin