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)
Kuchan
M J
MJ
Department of Chemical Engineering, Pennsylvania State University, University Park 16802.
Frangos
J A
JA
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