Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells.
The effect of shear stress on the release of endothelin-1 (ET-1) from endothelial cells is at present controversial with various investigators observing an increase and others observing a decrease. Our data reveal that the release of ET-1 from primary cultures of human umbilical vein endothelial cells varies with the duration and the level of shear. Sustained exposure to low levels of shear (1.8 dyn/cm2) or a brief exposure (< 1 h) to 10 dyn/cm2 caused a sustained stimulation of ET-1 release. Staurosporine (STPN) completely blocked the stimulation in both cases, suggesting that ET-1 release is increased via activation of protein kinase C (PKC). Exposure to 6-25 dyn/cm2 for > or = 6 h dramatically inhibited ET-1 release and led to 0-70% inhibition of cumulative release by 16 h. Pretreatment with N omega-nitro-L-arginine (L-NNA) reversed this suppression in a dose-dependent manner, implicating either nitric oxide (NO) and/or guanosine 3',5'-cyclic monophosphate (cGMP) as a requirement for shear-mediated inhibition of ET-1 release. Treatment of stationary cultures with 8-bromo-cGMP and atrial natriuretic peptide mimicked the inhibition of ET-1 release caused by shear and revealed that cGMP is capable of inhibiting ET-1. Likewise, the inhibitory effects of shear were potentiated and diminished by 3-isobutyl-1-methylxanthine (IBMX) and methylene blue, respectively. Thus cGMP also appears to exert an inhibitory effect in cells exposed to shear.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Chemical Engineering, Pennsylvania State University, University Park 16802.
M J
MJ
Kuchan
J A
JA
Frangos
D000255:Adenosine Triphosphate / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology*; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D013314:Stress, Mechanical
D016232:Endothelins; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D011493:Protein Kinase C; D006152:Cyclic GMP