Abstract
The cellular and molecular basis of growth hormone (GH) actions on the heart remain poorly defined, and it is unclear whether GH effects on the myocardium are direct or mediated at least in part via insulin-like growth factor (IGF-1). Here, we demonstrate that the cultured neonatal cardiomyocyte is not an appropriate model to study the effects of GH because of artifactual loss of GH receptors (GHRs). To circumvent this problem, rat neonatal cardiomyocytes were infected with a recombinant adenovirus expressing the murine GHR. Functional integrity of GHR was suggested by GH-induced activation of the cognate JAK2/STAT5, MAPK, and Akt intracellular pathways in the cells expressing GHR. Although exposure to GH resulted in a significant increase in the size of the cardiomyocyte and increased expression of c-fos, myosin light chain 2, and skeletal alpha-actin mRNAs, there were no significant changes in IGF-1 or atrial natriuretic factor mRNA levels in response to GH stimulation. In this model, GH increased incorporation of leucine, uptake of palmitic acid, and abundance of fatty acid transport protein mRNA. In contrast, GH decreased uptake of 2-deoxy-d-glucose and levels of Glut1 protein. Thus, in isolated rat neonatal cardiomyocytes expressing GHR, GH induces hypertrophy and causes alterations in cellular metabolic profile in the absence of demonstrable changes in IGF-1 mRNA, suggesting that these effects may be independent of IGF-1.
Highlights
The cellular and molecular basis of growth hormone (GH) actions on the heart remain poorly defined, and it is unclear whether GH effects on the myocardium are direct or mediated at least in part via insulin-like growth factor (IGF-1)
We demonstrate that GH stimulates hypertrophy of the isolated cardiomyocyte, and these actions of GH seem to be largely independent of changes in IGF-1 gene expression, findings that support an important independent role for the GH/GH receptors (GHRs) axis in normal cardiac growth
We demonstrate that GH has effects on the isolated neonatal cardiomyocyte expressing GHR
Summary
In support of a direct (i.e. not secondary to stimulation of circulating IGF-1) effect of GH on cardiac function is the demonstration that ex vivo perfusion of the isolated rat heart with GH results in enhanced protein synthesis [21] At present, it is not known if GH, acting through its cognate receptor (growth hormone receptor (GHR)), has direct effects on the heart or if some or all of the observed cardiovascular effects of GH administration are secondary to an increase in circulating levels of IGF-1 and/or hemodynamic changes in vascular tone and blood pressure [22]. We have developed such a model by exploiting the strategy of recombinant adenovirus-mediated overexpression of GHR in neonatal rat cardiomyocytes Using this model, we demonstrate that GH stimulates hypertrophy of the isolated cardiomyocyte, and these actions of GH seem to be largely independent of changes in IGF-1 gene expression, findings that support an important independent role for the GH/GHR axis in normal cardiac growth. GH alters the metabolic profile of rat neonatal cardiomyocytes by inhibiting glucose uptake, stimulating fatty acid uptake, and increasing protein synthesis, changes that facilitate both postnatal cardiac growth and maturation of myocardial metabolism
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