title: p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation.
abstract: p27(kip1) (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Ningtian
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yunle
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Pengsheng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006239:Haplotypes; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017228:Hepatocyte Growth Factor; D051550:I-kappa B Kinase
references.citation: J Mol Cell Cardiol. 1998 Oct;30(10):2121-35
references.pmid: 9799664
references.citation: Ciba Found Symp. 1997;212:215-26; discussion 227-9
references.pmid: 9524773
references.citation: J Cell Biol. 1992 Nov;119(3):629-41
references.pmid: 1383237
references.citation: Nature. 1998 Nov 12;396(6707):177-80
references.pmid: 9823898
references.citation: Nature. 2014 May 1;509(7498):15-6
references.pmid: 24784193
references.citation: Cell. 1996 May 31;85(5):733-44
references.pmid: 8646781
references.citation: Circulation. 1998 Nov 10;98(19):2081-7
references.pmid: 9808608
references.citation: J Mol Cell Cardiol. 2007 Apr;42(4):706-21
references.pmid: 17362983
references.citation: Circ Res. 2002 May 31;90(10):1044-54
references.pmid: 12039793
references.citation: Science. 1996 Nov 1;274(5288):782-4
references.pmid: 8864118
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5456-61
references.pmid: 10779546
references.citation: Cancer Res. 2006 Feb 15;66(4):2162-72
references.pmid: 16489017
references.citation: Heart. 2010 May;96(10):792-800
references.pmid: 20448133
references.citation: Circ Res. 2010 Oct 1;107(7):923-33
references.pmid: 20671234
references.citation: Cell. 1996 May 31;85(5):707-20
references.pmid: 8646779
references.citation: J Mol Cell Cardiol. 2004 Apr;36(4):547-59
references.pmid: 15081314
references.citation: FASEB J. 2001 Sep;15(11):1989-95
references.pmid: 11532979
references.citation: Circ Res. 2005 Oct 28;97(9):937-45
references.pmid: 16195480
references.citation: Cell Cycle. 2003 Mar-Apr;2(2):91-5
references.pmid: 12695654
references.citation: Kidney Int. 1999 Sep;56(3):794-814
references.pmid: 10469350
references.citation: J Mol Cell Cardiol. 2011 May;50(5):742-50
references.pmid: 20600100
references.citation: Circ Res. 1999 Jul 23;85(2):117-27
references.pmid: 10417393
references.citation: J Am Heart Assoc. 2012 Dec;1(6):e005652
references.pmid: 23316332
references.citation: Cell Cycle. 2005 Oct;4(10):1360-3
references.pmid: 16138008
references.citation: Nat Med. 1995 Oct;1(10):1085-9
references.pmid: 7489368
references.citation: Circulation. 2009 Jan 27;119(3):e21-181
references.pmid: 19075105
references.citation: Oncogene. 1997 May 1;14(17):2025-32
references.pmid: 9160882
references.citation: Nat Med. 1996 May;2(5):534-9
references.pmid: 8616711
references.citation: Biochem Biophys Res Commun. 2014 May 16;447(4):563-8
references.pmid: 24751519
references.citation: Cell. 1996 May 31;85(5):721-32
references.pmid: 8646780
references.citation: J Biomed Res. 2010 May;24(3):198-206
references.pmid: 23554631
references.citation: J Biol Chem. 2005 Sep 9;280(36):31548-56
references.pmid: 16014626
references.citation: Exp Cell Res. 2001 Mar 10;264(1):148-68
references.pmid: 11237531
references.citation: J Mol Cell Cardiol. 1998 Mar;30(3):463-74
references.pmid: 9515024
references.citation: J Biol Chem. 2011 Mar 11;286(10):8644-8654
references.pmid: 21209082
references.citation: Development. 2014 Apr;141(8):1649-59
references.pmid: 24715455
references.citation: Circulation. 1998 Feb 24;97(7):645-50
references.pmid: 9495299
references.citation: Mol Vis. 2014 Jan 06;20:24-37
references.pmid: 24426773
references.citation: Circulation. 1998 Dec 22-29;98(25):2800-4
references.pmid: 9860779
references.citation: Cancer Lett. 2009 Mar 8;275(1):139-49
references.pmid: 19038492
references.citation: Cancer Cell. 2013 May 13;23(5):647-59
references.pmid: 23602409
references.citation: Int J Cardiol. 1998 Dec 1;67(2):133-42
references.pmid: 9891946
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2064-9
references.pmid: 21245320
references.citation: J Clin Invest. 1994 Aug;94(2):623-30
references.pmid: 7518840
references.citation: Nature. 2004 Apr 8;428(6983):664-8
references.pmid: 15034593