Regulation of prostacyclin synthesis by angiotensin II and TNF-alpha in vascular smooth muscle.
We had previously established that in a model of Ang II-induced hypertension, administration of an anti-TNF-alpha antibody caused additional increases in mean arterial pressure. Production of vasodilator prostanoids (i.e. PGI2 and PGE2) is increased by Ang II in vascular smooth muscle and is part of a counter-regulatory mechanism that opposes increases in vascular tone. We, therefore, examined the effects of TNF-alpha on Ang II-induced increases in PGI2 production in vascular smooth muscle cells (VSMC). Addition of Ang II caused an increase in the production of PGI2, while addition of TNF-alpha had no effect. However, pretreatment with TNF-alpha potentiated the stimulatory effects of Ang II. The potentiating effect of TNF-alpha was neither at the level of prostacyclin synthetase nor at the level of acyl hydrolase activity. This potentiation was dependent on tyrosine kinase activity, as preincubation with genistein completely abolished the effect of TNF-alpha. TNF-alpha upregulated AA-induced PGI2 synthesis, indicating that the effect of TNF-alpha is at the level of cyclooxygenase (COX). These data suggest that TNF-alpha potentiates Ang II-induced synthesis of PGI2 and PGE2 in a tyrosine kinase-dependent manner, an effect that may contribute to the counter-regulatory influence of prostaglandins on the pressor effects of Ang II in the vasculature.
Askari
B
B
Department of Pathology, University of Washington School of Medicine, Seattle 98125, USA.
Ferreri
N R
NR
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D019833:Genistein / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019833:Genistein; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase