title: Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction.
abstract: Senescence is a recognized mechanism of cardiovascular diseases; however, its contribution to myocardial fibrosis and rupture after infarction and the underlying mechanisms remain unclear. Here we showed that senescent cardiac fibroblasts markedly accumulated in heart after myocardial infarction. The expression of key senescence regulators, especially p53, was significantly up-regulated in the infarcted heart or hypoxia-treated fibroblasts. Furthermore, knockdown of endogenous p53 by siRNA in fibroblasts markedly reduced hypoxia-induced cell senescence, cytokine expression but increased collagen expression, whereas increased expression of p53 protein by adenovirus infection had opposite effects. Consistent with in vitro results in cardiac fibroblasts, p53 deficiency in vivo significantly decreased the accumulation of senescent fibroblasts, the infiltration of macrophages and matrix metalloproteinases, but enhanced collagen deposition after myocardial infarction. In conclusion, these results suggest that the p53-mediated fibroblast senescence limits cardiac collagen production, and inhibition of p53 activity could represent a novel therapeutic target to increase reparative fibrosis and to prevent heart rupture after myocardial infarction.
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing, China.
authors.forename: Fuli
authors.initials: F
authors.lastname: Zhu
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Junmeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Piao
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D002465:Cell Movement; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D003094:Collagen
references.citation: Pharmacol Ther. 2009 Aug;123(2):255-78
references.pmid: 19460403
references.citation: Int J Nephrol. 2012;2012:154397
references.pmid: 23050148
references.citation: J Biol Chem. 2009 Feb 27;284(9):5488-96
references.pmid: 19117950
references.citation: Am J Hypertens. 2011 Jun;24(6):701-7
references.pmid: 21436792
references.citation: Nat Cell Biol. 2010 Jul;12(7):676-85
references.pmid: 20526329
references.citation: J Mol Cell Cardiol. 2004 Feb;36(2):175-83
references.pmid: 14871544
references.citation: Lab Invest. 2005 Apr;85(4):502-11
references.pmid: 15711569
references.citation: Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012 Jul;26(7):796-802
references.pmid: 22905613
references.citation: Curr Med Chem. 2006;13(16):1877-93
references.pmid: 16842199
references.citation: Cancer Res. 2005 Mar 1;65(5):1627-30
references.pmid: 15753354
references.citation: Blood. 2005 Jul 1;106(1):75-85
references.pmid: 15769896
references.citation: Cell. 2008 Aug 22;134(4):657-67
references.pmid: 18724938
references.citation: Am J Hypertens. 2012 Sep;25(9):994-1001
references.pmid: 22717542
references.citation: J Biol Chem. 2011 Oct 21;286(42):36396-403
references.pmid: 21880712
references.citation: PLoS One. 2012;7(5):e35144
references.pmid: 22574112
references.citation: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1015-26
references.pmid: 16617141
references.citation: Exp Cell Res. 1965 Mar;37:614-36
references.pmid: 14315085
references.citation: Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13314-8
references.pmid: 22847439
references.citation: Cardiovasc Res. 2006 Jun 1;70(3):457-65
references.pmid: 16533502
references.citation: Circ Res. 2010 Dec 10;107(12):1445-53
references.pmid: 20966393
references.citation: Diabetes. 2005 May;54(5):1423-8
references.pmid: 15855329
references.citation: Ann N Y Acad Sci. 2004 Jun;1019:330-2
references.pmid: 15247038
references.citation: Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1662-74
references.pmid: 22556333
references.citation: Circ Res. 2006 Sep 29;99(7):675-91
references.pmid: 17008597
references.citation: Cardiovasc Res. 2005 Jan 1;65(1):40-51
references.pmid: 15621032
references.citation: Cell Death Dis. 2011 May 26;2:e164
references.pmid: 21614094
references.citation: Nature. 1997 Sep 18;389(6648):300-5
references.pmid: 9305847
references.citation: Cell. 2007 Jul 27;130(2):223-33
references.pmid: 17662938
references.citation: FASEB J. 2005 Jun;19(8):1030-2
references.pmid: 15811878
references.citation: Blood. 2011 Jan 13;117(2):459-69
references.pmid: 20952688
references.citation: Mol Cancer Res. 2011 May;9(5):538-44
references.pmid: 21385881
references.citation: Cancer Metastasis Rev. 2010 Jun;29(2):273-83
references.pmid: 20390322
references.citation: J Clin Invest. 1997 Jun 1;99(11):2635-43
references.pmid: 9169493
references.citation: Radiat Res. 2005 Jan;163(1):53-62
references.pmid: 15606307
references.citation: Acta Pharmacol Sin. 2007 Jan;28(1):44-51
references.pmid: 17184581
references.citation: Trends Mol Med. 2010 May;16(5):238-46
references.pmid: 20444648
references.citation: Circulation. 2003 Sep 16;108(11):1395-403
references.pmid: 12975244
references.citation: Cell Signal. 2009 Mar;21(3):378-83
references.pmid: 18992324
references.citation: Circulation. 1997 Nov 18;96(10):3294-9
references.pmid: 9396419
references.citation: Am J Physiol Heart Circ Physiol. 2002 Feb;282(2):H615-21
references.pmid: 11788410
references.citation: Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1675-86
references.pmid: 22556335
references.citation: Genes Dev. 1998 Oct 1;12(19):3008-19
references.pmid: 9765203
references.citation: Apoptosis. 2009 Oct;14(10):1245-54
references.pmid: 19669889
references.citation: Circ Res. 2007 Jan 5;100(1):15-26
references.pmid: 17204661