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Abstract
Hypertension and myocardial infarction are associated with the onset of hypertrophy. Hypertrophy is a compensatory response mechanism to increases in mechanical load due to pressure or volume overload. It is characterized by extracellular matrix remodeling and hypertrophic growth of adult cardiomyocytes. Production of Vascular Endothelial Growth Factor (VEGF), which acts as an angiogenic factor and a modulator of cardiomyocyte function, is regulated by mechanical stretch. Mechanical stretch promotes VEGF secretion in neonatal cardiomyocytes. Whether this effect is retained in adult cells and the molecular mechanism mediating stretch-induced VEGF secretion has not been elucidated. Our objective was to investigate whether cyclic mechanical stretch induces VEGF secretion in adult cardiomyocytes and to identify the molecular mechanism mediating VEGF secretion in these cells. Isolated primary adult rat cardiomyocytes (ARCMs) were subjected to cyclic mechanical stretch at an extension level of 10% at 30 cycles/min that induces hypertrophic responses. Cyclic mechanical stretch induced a 3-fold increase in VEGF secretion in ARCMs compared to non-stretch controls. This increase in stretch-induced VEGF secretion correlated with NFkB activation. Cyclic mechanical stretch-mediated VEGF secretion was blocked by an NFkB peptide inhibitor and expression of a dominant negative mutant IkBα, but not by inhibitors of the MAPK/ERK1/2 or PI3K pathways. Chromatin immunoprecipitation assays demonstrated an interaction of NFkB with the VEGF promoter in stretched primary cardiomyocytes. Moreover, VEGF secretion is increased in the stretched myocardium during pressure overload-induced hypertrophy. These findings are the first to demonstrate that NFkB activation plays a role in mediating VEGF secretion upon cyclic mechanical stretch in adult cardiomyocytes. Signaling by NFkB initiated in response to cyclic mechanical stretch may therefore coordinate the hypertrophic response in adult cardiomyocytes. Elucidation of this novel mechanism may provide a target for developing future pharmacotherapy to treat hypertension and heart disease.
Highlights
Cardiovascular diseases such as myocardial infarction and hypertension often present with the development of cardiac hypertrophy
To investigate whether cyclic mechanical stretch induced Vascular Endothelial Growth Factor (VEGF) secretion in vitro, we measured the concentration of VEGF in the conditioned media from isolated adult rat cardiomyocytes (ARCMs) subjected to cyclic stretch or non-stretched controls
The present study demonstrates for the first time that hypertrophic mechanical stretch promotes VEGF secretion through the NFkB signal transduction pathway in adult rat cardiomyocytes
Summary
Cardiovascular diseases such as myocardial infarction and hypertension often present with the development of cardiac hypertrophy. In vivo mechanical stretch induces growth and remodeling within the hemodynamically overloaded myocardium [3,4] This can be partially modeled in vitro when cardiomyocytes are cultured on ECM-coated flexible membranes and subjected to mechanical stretch that is similar to stretch overload in vivo [5]. In these assays, mechanical stretch of cardiomyocytes activates several hypertrophic responses including increased gene expression of brain natriuretic peptide [BNP] and atrial natriuretic peptide [6], endothelin-1 [7] and upregulation of growth factors and cytokines [8,9]
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