title: Fat-derived factor omentin stimulates endothelial cell function and ischemia-induced revascularization via endothelial nitric oxide synthase-dependent mechanism.
abstract: Obesity-related diseases are associated with vascular dysfunction and impaired revascularization. Omentin is a fat-derived secreted protein, which is down-regulated in association with obese complications. Here, we investigated whether omentin modulates endothelial cell function and revascularization processes in vitro and in vivo. Systemic delivery of an adenoviral vector expressing omentin (Ad-omentin) enhanced blood flow recovery and capillary density in ischemic limbs of wild-type mice in vivo, which were accompanied by increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In cultured human umbilical vein endothelial cells (HUVECs), a physiological concentration of recombinant omentin protein increased differentiation into vascular-like structures and decreased apoptotic activity under conditions of serum starvation. Treatment with omentin protein stimulated the phosphorylation of Akt and eNOS in HUVECs. Inhibition of Akt signaling by treatment with dominant-negative Akt or LY294002 blocked the stimulatory effects of omentin on differentiation and survival of HUVECs and reversed omentin-stimulated eNOS phosphorylation. Pretreatment with the NOS inhibitor also reduced the omentin-induced increase in HUVEC differentiation and survival. Omentin protein also stimulated the phosphorylation of AMP-activated protein kinase in HUVECs. Transduction with dominant-negative AMP-activated protein kinase diminished omentin-induced phosphorylation of Akt and omentin-stimulated increase in HUVEC differentiation and survival. Of importance, in contrast to wild-type mice, systemic administration of Ad-omentin did not affect blood flow in ischemic muscle in eNOS-deficient mice in vivo. These data indicate that omentin promotes endothelial cell function and revascularization in response to ischemia through its ability to stimulate an Akt-eNOS signaling pathway.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Cardiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Sonomi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: rshibata@med.nagoya-u.ac.jp.
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kikuchi
authors.affiliation: Department of Cardiology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.affiliation: Department of Cardiology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Rokutanda
authors.affiliation: Department of Cardiology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Araki
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kataoka
authors.affiliation: Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Cardiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
authors.affiliation: Department of Biomedical Informatics, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.affiliation: Department of Cardiology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: nouchi@med.nagoya-u.ac.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology; D002454:Cell Differentiation; D002470:Cell Survival; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D058851:GPI-Linked Proteins; C432397:ITLN1 protein, human; D037102:Lectins; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
references.citation: J Clin Invest. 2000 Aug;106(4):493-9
references.pmid: 10953024
references.citation: Hypertens Res. 2011 Dec;34(12):1309-12
references.pmid: 21814208
references.citation: Int J Obes Relat Metab Disord. 2003 Dec;27(12):1541-5
references.pmid: 14634687
references.citation: J Neuroendocrinol. 2010 Mar;22(3):175-80
references.pmid: 20059648
references.citation: J Biol Chem. 2010 Feb 12;285(7):4387-97
references.pmid: 20018878
references.citation: Circ Res. 2002 Jun 28;90(12):1243-50
references.pmid: 12089061
references.citation: J Biol Chem. 2007 Jul 13;282(28):20351-64
references.pmid: 17519230
references.citation: Diabetes Res Clin Pract. 2010 Apr;88(1):29-33
references.pmid: 20129687
references.citation: Curr Opin Lipidol. 2003 Dec;14(6):561-6
references.pmid: 14624132
references.citation: J Biol Chem. 2011 Oct 7;286(40):34552-8
references.pmid: 21849507
references.citation: Circulation. 2009 Oct 20;120(16):1606-15
references.pmid: 19805648
references.citation: J Biol Chem. 2008 Dec 5;283(49):33902-10
references.pmid: 18801732
references.citation: Diabetes. 2007 Jun;56(6):1655-61
references.pmid: 17329619
references.citation: J Biol Chem. 2002 Oct 4;277(40):37670-7
references.pmid: 12163490
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14795-9
references.pmid: 8962134
references.citation: J Clin Invest. 1998 Jun 1;101(11):2567-78
references.pmid: 9616228
references.citation: Biochem Biophys Res Commun. 2011 May 6;408(2):339-43
references.pmid: 21514279
references.citation: Circulation. 2003 Sep 30;108(13):1546-51
references.pmid: 14517150
references.citation: Nitric Oxide. 2002 Nov;7(3):149-64
references.pmid: 12381413
references.citation: J Biol Chem. 2004 Jul 2;279(27):28670-4
references.pmid: 15123726
references.citation: Diabetologia. 1995 Apr;38(4):413-21
references.pmid: 7796981
references.citation: J Biol Chem. 2001 Jun 29;276(26):23456-63
references.pmid: 11313366
references.citation: Science. 2003 Feb 7;299(5608):856-8
references.pmid: 12574619
references.citation: Am Heart J. 1993 May;125(5 Pt 2):1494-7
references.pmid: 8480620
references.citation: Biochim Biophys Acta. 2005 Dec 30;1732(1-3):96-102
references.pmid: 16386808
references.citation: Nat Rev Immunol. 2011 Feb;11(2):85-97
references.pmid: 21252989
references.citation: J Biol Chem. 2004 Jan 9;279(2):1304-9
references.pmid: 14557259
references.citation: Circulation. 2007 Feb 13;115(6):752-62
references.pmid: 17261656
references.citation: Acta Pharmacol Sin. 2011 Jul;32(7):873-8
references.pmid: 21602837
references.citation: Nature. 1999 Jun 10;399(6736):597-601
references.pmid: 10376602
references.citation: J Biol Chem. 2008 Nov 21;283(47):32802-11
references.pmid: 18718903
references.citation: Diabetes Res Clin Pract. 2011 Jul;93(1):21-5
references.pmid: 21497934
references.citation: Biochem Biophys Res Commun. 2010 Mar 19;393(4):668-72
references.pmid: 20170632
references.citation: Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1253-61
references.pmid: 16531507
references.citation: Obesity (Silver Spring). 2011 Aug;19(8):1552-9
references.pmid: 21293447