Expression of immediate early genes, GATA-4, and Nkx-2.5 in adrenergic-induced cardiac hypertrophy and during regression in adult mice

1 Adrenoreceptor agonists induce a hypertrophic phenotype in vitro and in v ivo. To investigate the molecular remodeling in chronic cardiac hypertrophy we infused adult male mice with vehicle, isoproterenol, phenylephrine or b oth agonists for 3, 7 or 14 days. 2 All drugs increased cardiac mass. After minipump removal cardiac mass reg ressed to control levels within 7 days after PE and ISO treatment whereas I SO + PE treated hearts were incompletely regressed. 3 ANF and beta-MHC, but not alpha-MHC, expression were increased by agonist s at all time points. GATA-4, Nkx-2.5, Egr-1, c-jun and c-fos expression we re increased after 3, 7 and 14 days of treatment. Expression was greatest a fter ISO+PE>>ISO>PE>vehicle infusion suggesting a synergistic effect of adr enoreceptor stimulation and indicating a greater effect of beta- than alpha -adrenergic action in vivo. 4 After PE or ISO drug withdrawal the HW/BW was normal and Egr-1, c-jun, c- fos and GATA-4, but not Nkx2.5, expression dropped to control levels. HW/BW regression was incomplete after ISO + PE and elevated levels of Egr-1, c-j un and Nkx2.5 expression remained. 5 A hydralazine-mediated reduction in blood pressure had no effect on the a gonist-induced cardiac hypertrophy or gene expression. 6 In conclusion, we found that continued agonist stimulation, and not blood pressure, is responsible for the maintained increase in gene expression. F urther, we found the decrease in gene expression in the regression after dr ug withdrawal was gene specific.