title: Increased JNK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced cardiac remodeling.
abstract: The in vivo signal transduction pathway, responsible for isoproterenol-induced cardiac hypertrophy or remodeling, remains to be clarified. The purpose of this study was to examine c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), activator protein-1 (AP-1) and nuclear factor-kappa B (NK-kappa B) DNA binding activity, which seem to be important in a signal transduction cascade upstream of the increased level of mRNA expression observed in isoproterenol-induced cardiac remodeling. Rats were continuously infused with saline and isoproterenol by intravenous injection (a short period; 0.5 microgram/kg/min) and an osmotic minipump (a long period; 0.5 or 3 mg/kg/day). Cardiac morphology was measured by echocardiography. JNK and ERK were measured by in gel kinase assay. AP-1 and NF-kappa B DNA binding activity was determined using an electrophoretic mobility shift assay. Echocardiogram showed that the thickness of the left ventricular anterior wall (AW) and left ventricular posterior wall (PW) increased at day 1 in low doses, and at day 1 in high doses. Isoproterenol significantly increased ERK and JNK activity at 15 min after intravenous infusion of 0.5 microgram/kg/min isoproterenol. At late phase about JNK and ERK activity, only a high dose of isoproterenol increased JNK. AP-1 DNA binding activities spurred by low or high doses of isoproterenol administration increased at 12 h, reached their peak of 24.1- and 37.1-fold (P < 0.01), respectively, at 24 h, and thereafter decreased. Although low doses of isoproterenol did not change the level of NF-kappa B DNA binding activities, high doses increased it to 10.9-fold (P < 0.01) at day 2. This study showed increased JNK, ERK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced cardiac remodeling. AP-1 may contribute to the isoproterenol-induced cardiac remodeling, and JNK or NF-kappa B may also play some roles in it.
authors.affiliation: First Department of Internal Medicine, Osaka City University Medical School, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takemoto
authors.forename: M
authors.initials: M
authors.lastname: Yoshiyama
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: T
authors.initials: T
authors.lastname: Omura
authors.forename: R
authors.initials: R
authors.lastname: Komatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Izumi
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000139:chemically induced / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D011674:Pulse; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D007545:Isoproterenol