No abstract

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.

Unroofing the anomalous coronary artery arising from the opposite sinus of valsalva can be done in infants with minimal morbidity and mortality. Longer follow-up is needed to assess long-term results.

DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, beta-integrin-, PKC-, and transforming growth factor-beta-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to 1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg.kg(-1).day(-1)) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist-stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload.