title: Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice.
abstract: To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Bryn
authors.initials: B
authors.lastname: Freund
authors.forename: Danielle
authors.initials: D
authors.lastname: Feather
authors.forename: Roman
authors.initials: R
authors.lastname: Abramov
authors.forename: I-Hsien
authors.initials: IH
authors.lastname: Wu
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Junko
authors.initials: J
authors.lastname: Yamamoto-Hiraoka
authors.forename: Jan
authors.initials: J
authors.lastname: Goldenbogen
authors.forename: Konstantinos B
authors.initials: KB
authors.lastname: Sotiropoulos
authors.forename: Allen
authors.initials: A
authors.lastname: Clermont
authors.forename: Pedro
authors.initials: P
authors.lastname: Geraldes
authors.forename: Claudia
authors.initials: C
authors.lastname: Dall'Osso
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: Mark
authors.initials: M
authors.lastname: Rekhter
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology*; D002448:Cell Adhesion; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012307:Risk Factors; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation
chemical_list: D001057:Apolipoproteins E; D007328:Insulin; D019010:Vascular Cell Adhesion Molecule-1
references.citation: Arterioscler Thromb Vasc Biol. 2000 Feb;20(2):402-9
references.pmid: 10669636
references.citation: J Clin Invest. 2006 Apr;116(4):1071-80
references.pmid: 16528409
references.citation: Circ Res. 2000 Feb 18;86(3):347-54
references.pmid: 10679488
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9114-9
references.pmid: 8799163
references.citation: Dev Biol. 2001 Feb 15;230(2):230-42
references.pmid: 11161575
references.citation: Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2187-94
references.pmid: 18802016
references.citation: Arterioscler Thromb Vasc Biol. 1998 Nov;18(11):1803-9
references.pmid: 9812921
references.citation: J Biol Chem. 1999 Jun 11;274(24):16741-6
references.pmid: 10358014
references.citation: Diabetologia. 2004 Mar;47(3):532-536
references.pmid: 14762656
references.citation: Diabetes. 2000 Mar;49(3):485-91
references.pmid: 10868972
references.citation: Am J Physiol Endocrinol Metab. 2001 Jun;280(6):E848-56
references.pmid: 11350766
references.citation: Circulation. 2000 Feb 15;101(6):676-81
references.pmid: 10673261
references.citation: J Clin Invest. 1995 Jul;96(1):60-8
references.pmid: 7542286
references.citation: Diabetes. 2008 Dec;57(12):3307-14
references.pmid: 18835939
references.citation: J Clin Invest. 1994 Sep;94(3):1172-9
references.pmid: 8083357
references.citation: J Clin Invest. 1996 Jun 1;97(11):2601-10
references.pmid: 8647954
references.citation: Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56
references.pmid: 17179929
references.citation: Am J Physiol. 1999 Jun;276(6):H1943-50
references.pmid: 10362674
references.citation: Circ Res. 1996 Feb;78(2):225-30
references.pmid: 8575065
references.citation: Circulation. 1996 May 15;93(10):1809-17
references.pmid: 8635260
references.citation: J Immunol. 2007 Jun 1;178(11):7405-11
references.pmid: 17513791
references.citation: Cell Metab. 2006 Apr;3(4):247-56
references.pmid: 16581002
references.citation: Cell Metab. 2006 Apr;3(4):257-66
references.pmid: 16581003
references.citation: N Engl J Med. 1996 Apr 11;334(15):952-7
references.pmid: 8596596
references.citation: J Biol Chem. 1991 Dec 5;266(34):23251-6
references.pmid: 1744120
references.citation: Diabetes. 2001 Nov;50(11):2611-8
references.pmid: 11679442
references.citation: Cell Metab. 2007 Dec;6(6):446-57
references.pmid: 18054314
references.citation: J Biol Chem. 2006 Nov 17;281(46):35544-53
references.pmid: 16980307
references.citation: J Clin Invest. 2003 May;111(9):1373-80
references.pmid: 12727929
references.citation: J Clin Invest. 1996 Aug 15;98(4):894-8
references.pmid: 8770859
references.citation: J Mol Cell Cardiol. 1998 Aug;30(8):1535-43
references.pmid: 9737940
references.citation: Diabetes. 2006 Mar;55(3):691-8
references.pmid: 16505232
references.citation: J Biol Chem. 1999 Jun 4;274(23):15982-5
references.pmid: 10347145
references.citation: J Lipid Res. 2008 Jun;49(6):1353-63
references.pmid: 18349418
references.citation: J Clin Endocrinol Metab. 2000 Jul;85(7):2572-5
references.pmid: 10902810
references.citation: Circ Res. 2009 May 8;104(9):1085-94
references.pmid: 19342603
references.citation: J Clin Invest. 2007 Jul;117(7):1961-7
references.pmid: 17557122
references.citation: J Cell Biol. 1998 Nov 16;143(4):1129-41
references.pmid: 9817767
references.citation: Circulation. 2001 May 29;103(21):2598-603
references.pmid: 11382730
references.citation: Diabetologia. 2002 Apr;45(4):556-9
references.pmid: 12032633
references.citation: J Clin Invest. 2007 Jun;117(6):1718-26
references.pmid: 17549259
references.citation: J Biol Chem. 2008 Dec 5;283(49):34327-36
references.pmid: 18854316
references.citation: Diabetes Obes Metab. 2007 Jul;9(4):455-63
references.pmid: 17587387
references.citation: J Clin Invest. 1999 Aug;104(4):447-57
references.pmid: 10449437
references.citation: Circulation. 1999 Aug 24;100(8):820-5
references.pmid: 10458717