Cardiac hypertrophy has been observed in newborn infants treated with
dexamethasone (DEX). This study was undertaken to examine whether DEX-induced
hypertrophy in newborn rats is associated with redistribution of
cardiac myosin heavy chain (MHC)
isoforms and, if so, the effects involve transcriptional regulation. Newborn rats were injected with either DEX (1 mg/kg/day; s.c.) or equivalent volume
normal saline for 1, 3, 5, 7 or 9 days.
Hypertrophy was quantified by heart dry/wet wt ratios, heart/body wt ratios, and total
protein content of the myocardium. Changes in the expression of cardiac MHC
mRNA were characterized by northern blot and slot blot analyses, using
isoform specific probes for alpha- and beta-MHC genes. DEX effect on alpha-MHC gene transcription was analyzed by transiently transfecting various alpha-MHC promoter/CAT reporter constructs into primary cultures of cardiac myocytes derived from one day old rat pups. DEX administration into newborn rats produced significant
cardiac hypertrophy ranging from 23% at day 1 to 59% at 9 days. The
hypertrophy was accompanied by immediate increase (83%) in steady state level of the alpha-MHC
mRNA within one day and a maximum increase (148%) at 7 days of treatment. The steady state level of beta-MHC
mRNA declined by 25% at day 1 and a maximum decrease of 54% at day 7 of DEX treatment. The changes in MHC
mRNA were also reflected in their
protein levels as determined by V1 and V3
isozyme analysis. DEX treatment of primary cultures of cardiomyocytes following transfection with alpha-MHC promoter/CAT reporter constructs resulted in increased CAT expression in a dose dependent manner. The minimum alpha-MHC gene sequences responding to DEX treatment were located between the -200 to -74-bp region of the gene, resulting in 2-fold and 6-fold activation of CAT reporter after 0.05 and 0.1 mM doses of DEX, respectively. Our data indicate that DEX induced
cardiac hypertrophy in newborn rats is accompanied by increased expression of alpha-MHC and decreased expression of beta-MHC. The alpha-MHC effects are mediated in part through transcriptional mechanisms.