Increased JNK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced cardiac remodeling

The in vivo signal transduction pathway, responsible for isoproterenol-indu ced cardiac hypertrophy or remodeling, remains to be clarified. The purpose of this study was to examine c-Jun NH2-terminal kinase (JNK) and extracell ular signal-regulated kinase (ERK), activator protein-1 (AP-1) and nuclear factor-kappa B (NK-kappa B) DNA binding activity, which seem to be importan t 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 mu g/kg/min) and an osmotic minipump (a long period; 0.5 or 3 mg/kg/day). Cardiac morphology was measured by echocardiography. J NK and ERK were measured by in gel kinase assay. AP-1 and NF-kappa B DNA bi nding 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 l ow doses, and at day 1 in high doses, Isoproterenol significantly increased ERK and JNK activity at 15 min after intravenous infusion of 0.5 mu g/kg/m in isoproterenol. At late phase about JNK and ERK activity, only a high dos e of isoproterenol increased JNK. AP-1 DNA binding activities spurred by lo w 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 ther eafter decreased. Although low doses of isoproterenol did not change the le vel of NF-kappa B DNA binding activities, high doses increased it to 10.9-f old (P<0.01) at day 2. This study showed increased JNK, ERK, AP-1 and NF-ka ppa B DNA binding activities in isoproterenol-induced cardiac remodeling. A P-1 may contribute to the isoproterenol-induced cardiac remodeling, and JNK or NF-kappa B may also play some roles in it. (C) 1999 Academic Press.