Contributory role of VEGF overexpression in endothelin-1-induced cardiomyocyte hypertrophy.
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 [(14)C]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 mug/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.
Shimojo
Nobutake
N
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Jesmin
Subrina
S
Zaedi
Sohel
S
Otsuki
Takeshi
T
Maeda
Seiji
S
Yamaguchi
Naoto
N
Aonuma
Kazutaka
K
Hattori
Yuichi
Y
Miyauchi
Takashi
T
D000818:Animals; D000831:Animals, Newborn; D002312:Cardiomyopathy, Hypertrophic / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D019332:Endothelin-1; D042461:Vascular Endothelial Growth Factor A