Dexamethasone induced cardiac hypertrophy in newborn rats is accompanied by changes in myosin heavy chain phenotype and gene transcription

Cardiac hypertrophy has been observed in newborn infants treated with dexam ethasone (DEX). This study was undertaken to examine whether DEX-induced hy pertrophy in newborn rats is associated with redistribution of cardiac myos in heavy chain (MHC) isoforms and if so, the effects involve transcriptiona l 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 iso form 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 myocy tes 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 s teady state level of the alpha-MHC mRNA within one day and a maximum increa se (148%) at 7 days of treatment. The steady state level of beta-MHC mRNA d eclined by 25% at day 1 and a maximum decrease of 54% at day 7 of DEX treat ment. The changes in MHC mRNA were also reflected in their protein levels a s determined by V1 and V3 isozyme analysis. DEX treatment of primary cultur es of cardiomyocytes following transfection with a-MHC promoter/CAT reporte r constructs resulted in increased CAT expression in a dose dependent manne r. The minimum alpha-MHC gene sequences responding to DEX treatment were lo cated between the -200 to -74-bp region of the gene, resulting in 2-fold an d 6-fold activation of CAT reporter after 0.05 and 0.1 mM doses of DEX, res pectively. Our data indicate that DEX induced cardiac hypertrophy in newbor n rats is accompanied by increased expression of alpha-MHC and decreased ex pression of beta-MHC. The alpha-MHC effects are mediated in part through tr anscriptional mechanisms.