title: Role of c-Jun NH2-terminal kinase in G-protein-coupled receptor agonist-induced cardiac plasminogen activator inhibitor-1 expression.
abstract: Plasminogen activator inhibitor-1 (PAI-1) has been implicated as a contributing risk factor for cardiovascular disease. However, little is known about molecular mechanisms of cardiac PAI-1 gene expression. To elucidate these mechanisms, dominant negative mutants of c-Jun NH(2)-terminal kinase (JNK), p38MAPK, apoptosis signal-regulating kinase-1 (ASK-1) and c-Jun were overexpressed in rat neonatal ventricular cardiac myocytes and fibroblasts by adenovirus vector to abrogate the activation of the corresponding endogenous proteins. One hundred nmol/l of angiotensin II significantly enhanced the JNK and p38MAPK activities of cardiomyocytes (2.3-fold and 1.9-fold, P < 0.05) and fibroblasts (3.2-fold and 2.5-fold, P < 0.05). At 3 h after stimulation, angiotensin II was found to have significantly increased PAI-1 mRNA, by 5.2-fold in cardiomyocytes and by 9.7-fold in fibroblasts. Dominant negative mutants of JNK, ASK-1 and c-Jun significantly inhibited PAI-1 mRNA expression and protein synthesis in both cardiomyocytes and fibroblasts, whereas a dominant negative mutant of p38MAPK did not change this expression. Moreover, a dominant negative mutant of JNK also significantly prevented the induction of PAI-1 mRNA expression by 100 nmol/l endothelin-1 and 10 micromol/l phenylephrine. In conclusion, G-protein-coupled receptor agonist-induced PAI-1 expression is partially mediated through JNK activation.
authors.affiliation: Department of Internal Medicine and Cardiology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. omura@med.osaka-cu.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Omura
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshiyama
authors.forename: Ryo
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Kusuyama
authors.forename: Soichiro
authors.initials: S
authors.lastname: Enomoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nishiya
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Masaru
authors.initials: M
authors.lastname: Motojima
authors.forename: Kaname
authors.initials: K
authors.lastname: Akioka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshikawa
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
chemical_list: D005419:Flavonoids; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one