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Contributory role of VEGF overexpression in endothelin-1-induced cardiomyocyte hypertrophy

¹Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan; ²Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, and ³Department of Pharmacology, School of Medicine, University of Toyama, Toyama, Japan

Submitted 25 August 2006 ; accepted in final form 16 March 2007

Although endothelin-1 (ET-1) stimulates vascular endothelial growth factor (VEGF) expression in a variety of cells, including endothelial cells and vascular smooth muscle cells, the effects of ET-1 on expression of VEGF and its receptors in cardiomyocytes are unknown. In the present study, we found that treatment of neonatal rat cardiomyocytes with ET-1 for 24 h resulted in upregulation of VEGF and its two principal receptors, fetal liver kinase 1 and fms-like tyrosine kinase 1, in a concentration-dependent manner (10^–12 to 10^–6 M). ET-1 treatment also caused significant cardiomyocyte hypertrophy, as indicated by increases in cell surface area and [¹⁴C]leucine uptake by cardiomyocytes. Treatment with TA-0201 (10^–6 M), an ET_A-selective blocker, eliminated ET-1-induced overexpression of VEGF and its receptors as well as cardiomyocyte hypertrophy. Treatment with VEGF neutralizing peptides (5–10 µg/ml) partially but significantly inhibited ET-1-induced cardiomyocyte hypertrophy. These results suggest that ET-1 treatment of cardiomyocytes promotes overexpression of VEGF and its receptors via activation of ET_A receptors, and consequently the upregulated VEGF signaling system appears to contribute, at least in part, to ET-1-induced cardiomyocyte hypertrophy.

ET_A receptor; hypoxia-inducible factor; VEGF neutralizing peptides

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