Adiponectin prevents diabetic premature senescence of endothelial progenitor cells and promotes endothelial repair by suppressing the p38 MAP kinase/p16INK4A signaling pathway.
OBJECTIVE
A reduced number of circulating endothelial progenitor cells (EPCs) are casually associated with the cardiovascular complication of diabetes. Adiponectin exerts multiple protective effects against cardiovascular disease, independent of its insulin-sensitizing activity. The objective of this study was to investigate whether adiponectin plays a role in modulating the bioavailability of circulating EPCs and endothelial repair.


METHODS
Adiponectin knockout mice were crossed with db(+/-) mice to produce db/db diabetic mice without adiponectin. Circulating number of EPCs were analyzed by flow cytometry. Reendothelialization was evaluated by staining with Evans blue after wire-induced carotid injury.


RESULTS
In adiponectin knockout mice, the number of circulating EPCs decreased in an age-dependent manner compared with the wild-type controls, and this difference was reversed by the chronic infusion of recombinant adiponectin. In db/db diabetic mice, the lack of adiponectin aggravated the hyperglycemia-induced decrease in circulating EPCs and also diminished the stimulatory effects of the PPARγ agonist rosiglitazone on EPC production and reendothelialization. In EPCs isolated from both human peripheral blood and mouse bone marrow, treatment with adiponectin prevented high glucose-induced premature senescence. At the molecular level, adiponectin decreased high glucose-induced accumulation of intracellular reactive oxygen species and consequently suppressed activation of p38 MAP kinase (MAPK) and expression of the senescence marker p16(INK4A).


CONCLUSIONS
Adiponectin prevents EPC senescence by inhibiting the ROS/p38 MAPK/p16(INK4A) signaling cascade. The protective effects of adiponectin against diabetes vascular complications are attributed in part to its ability to counteract hyperglycemia-mediated decrease in the number of circulating EPCs.
Chang
Junlei
J
Department of Medicine, University of Hong Kong, Hong Kong, China.
Li
Yiming
Y
Huang
Yu
Y
Lam
Karen S L
KS
Hoo
Ruby L C
RL
Wong
Wing Tak
WT
Cheng
Kenneth K Y
KK
Wang
Yiqun
Y
Vanhoutte
Paul M
PM
Xu
Aimin
A
D052242:Adiponectin / Q000172:deficiency / Q000627:therapeutic use*; D000375:Aging; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002339:Carotid Arteries / Q000601:surgery; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011817:Rabbits; D054411:Receptors, Leptin / Q000172:deficiency / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D052242:Adiponectin; D000911:Antibodies, Monoclonal; D019941:Cyclin-Dependent Kinase Inhibitor p16; D054411:Receptors, Leptin; D048051:p38 Mitogen-Activated Protein Kinases
N Engl J Med. 2003 Feb 13;348(7):593-600
12584367
Science. 1997 Feb 14;275(5302):964-7
9020076
Cardiovasc Res. 2009 Jun 1;82(3):421-9
19261622
Biochem J. 2008 Feb 1;409(3):623-33
18177270
Hepatology. 2008 Feb;47(2):677-85
18220291
Diabetes. 2007 Oct;56(10):2609-15
17623816
Nature. 2006 Sep 28;443(7110):421-6
16957735
Nat Med. 2004 Dec;10(12):1384-9
15558058
Circulation. 2003 Mar 4;107(8):1164-9
12615796
Diabetes. 2006 Jun;55(6):1840-6
16731851
Diabetes. 2004 Mar;53(3):585-90
14988241
Nat Med. 2004 Aug;10(8):858-64
15235597
Nat Med. 2005 Oct;11(10):1096-103
16155579
Br J Pharmacol. 2008 Feb;153(4):636-45
17906687
FEBS Lett. 2009 Aug 6;583(15):2457-63
19596003
Diabetes. 2008 Mar;57(3):724-31
18086900
Trends Cardiovasc Med. 2008 Jan;18(1):33-7
18206807
Diabetes. 2006 Jan;55(1):120-7
16380484
Circulation. 2004 Mar 23;109(11):1392-400
14993120
Hepatology. 2008 Oct;48(4):1087-96
18698578
N Engl J Med. 2005 Sep 8;353(10):999-1007
16148285
Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1789-95
18599796
Circulation. 2007 Mar 20;115(11):1408-16
17339545
Diabetes. 2007 Jun;56(6):1559-68
17389326
Diabetes Care. 2007 May;30(5):1305-13
17277037
Circulation. 2008 Jan 15;117(2):216-23
18158361
Circulation. 2005 Mar 8;111(9):1184-91
15753227
Diabetes. 2004 Jan;53(1):195-9
14693715
Diabetes. 2008 Dec;57(12):3222-30
18835932
J Clin Invest. 2006 Jul;116(7):1784-92
16823476
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2627-33
17916771
J Biol Chem. 2002 Sep 20;277(38):34658-61
12151381
Circulation. 2002 Nov 26;106(22):2781-6
12451003
Nat Med. 2006 Apr;12(4):446-51
16565722
Circ J. 2006 Aug;70(8):1076-81
16864945
Blood. 2007 Mar 1;109(5):1801-9
17053059
Endocrinology. 2002 Mar;143(3):998-1007
11861525
J Biol Chem. 2008 Apr 18;283(16):10930-8
18227068
Circ J. 2007 Sep;71(9):1376-82
17721014
Diabetes Res Clin Pract. 2006 Sep;73(3):310-4
16631275
FEBS Lett. 2008 May 14;582(11):1607-12
18423403
Circulation. 2007 Jul 10;116(2):163-73
17592079
Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):288-93
14699017
J Clin Invest. 2003 Jul;112(1):91-100
12840063
Diabetes. 2007 May;56(5):1387-94
17287464
Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):698-703
15662022
FASEB J. 2009 May;23(5):1358-65
19124561