title: ERK-MAPK signaling opposes rho-kinase to reduce cardiomyocyte apoptosis in heart ischemic preconditioning.
abstract: We and others have reported that Rho-kinase plays an important role in the pathogenesis of heart ischemia/reperfusion (I/R) injury. Studies have also demonstrated that the activation of Rho-kinase is reversed in ischemic preconditioning (IPC). However, the mechanisms by which Rho-kinase is increased in I/R and reversed in IPC are not thoroughly understood. In female Wistar rats, we created I/R by ligating the left anterior-descending branch of the coronary artery (LAD) for 30 min and releasing the ligature for 180 min. IPC rats underwent IPC (two cycles of 5-min ligation of the LAD and 5-min reflow) before I/R. IPC caused a significant increase in extracellular signal-regulated kinase (ERK)1/2 activity and reduced Rho-kinase activity and cardiomyocyte apoptosis (P<0.05 versus I/R). Administration of PD98059, an inhibitor of ERK-mitogen-activated protein kinase (MAPK), increased cardiomyocyte apoptosis, Caspase-3 activity and myocardial infarction size (P<0.05 versus IPC). Western-blot analysis showed that administration of PD98059 increased Rho-kinase activity. Treatment with fasudil, an inhibitor of Rho-kinase, reversed cell apoptosis caused by treatment with PD98059 in IPC. In addition, ROCK1 (Rho-kinase 1) may be the major Rho-kinase isoform that is opposed by ERK-MAPK signaling in IPC. These results indicate that ERK-MAPK signaling is required in IPC to oppose Rho-kinase activity in cardiomyocyte apoptosis in vivo.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research of the Chinese Ministry of Education and Public Health, Shandong University Qilu Hospital, Shandong Province, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Bian
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Li
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Liu
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Sun
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Ji
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D019157:Ischemic Preconditioning, Myocardial; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D005419:Flavonoids; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D020742:rhoA GTP-Binding Protein; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
references.citation: Circulation. 1986 Nov;74(5):1124-36
references.pmid: 3769170
references.citation: Biotechniques. 1993 Sep;15(3):532-4, 536-7
references.pmid: 7692896
references.citation: J Mol Cell Cardiol. 2002 Jun;34(6):661-8
references.pmid: 12054853
references.citation: Am J Physiol Heart Circ Physiol. 2001 Oct;281(4):H1508-23
references.pmid: 11557539
references.citation: Circ Res. 2000 Mar 31;86(6):692-9
references.pmid: 10747006
references.citation: Circulation. 2004 Apr 27;109(16):1938-41
references.pmid: 15096454
references.citation: EMBO J. 2001 Feb 15;20(4):755-66
references.pmid: 11179220
references.citation: J Biochem. 2004 Nov;136(5):557-61
references.pmid: 15632293
references.citation: J Biol Chem. 2003 Dec 12;278(50):49911-9
references.pmid: 14514696
references.citation: J Clin Invest. 2004 Oct;114(7):937-43
references.pmid: 15467832
references.citation: EMBO J. 1996 May 1;15(9):2208-16
references.pmid: 8641286
references.citation: Cancer Cell. 2003 Jul;4(1):67-79
references.pmid: 12892714
references.citation: Circ Res. 2002 Nov 1;91(9):776-81
references.pmid: 12411391
references.citation: Cancer Cell. 2006 Jan;9(1):33-44
references.pmid: 16413470
references.citation: Clin Chim Acta. 2009 Mar;401(1-2):76-80
references.pmid: 19061880
references.citation: BMC Complement Altern Med. 2006 Feb 19;6:3
references.pmid: 16504000
references.citation: Eur J Pharmacol. 2005 Dec 19;527(1-3):129-40
references.pmid: 16307738
references.citation: J Cell Biol. 1998 Nov 30;143(5):1249-58
references.pmid: 9832553
references.citation: Nat Cell Biol. 2001 Apr;3(4):339-45
references.pmid: 11283606
references.citation: J Cell Mol Med. 2008 Aug;12(4):1220-8
references.pmid: 18782186
references.citation: Science. 1997 Feb 28;275(5304):1308-11
references.pmid: 9036856
references.citation: Circ Res. 2006 Feb 17;98(3):322-34
references.pmid: 16484628
references.citation: J Biol Chem. 1995 Nov 17;270(46):27489-94
references.pmid: 7499206
references.citation: Gut. 2005 Jun;54(6):814-22
references.pmid: 15888791
references.citation: Circulation. 2004 Aug 10;110(6):718-23
references.pmid: 15289381
references.citation: Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):2111-24
references.pmid: 17034354
references.citation: J Cell Biol. 2005 Dec 19;171(6):1013-22
references.pmid: 16365167
references.citation: Cardiovasc Res. 2004 Feb 15;61(3):548-58
references.pmid: 14962485
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12825-30
references.pmid: 16908865
references.citation: Circulation. 2004 Jul 6;110(1):51-7
references.pmid: 15210595
references.citation: Science. 1990 Jul 6;249(4964):64-7
references.pmid: 2164259
references.citation: Acta Pharmacol Sin. 2004 Mar;25(3):306-12
references.pmid: 15000883
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H971-6
references.pmid: 15358610
references.citation: Cardiovasc Res. 2004 Feb 15;61(3):448-60
references.pmid: 14962476