Molecular mechanism of the desensitization of beta-adrenergic receptors and adenilate cyclase by hypoxia in human endothelial cells.
Long-term oxygen deficiency in vivo leads to the progressive blunting of responsiveness to sympathetic stimulation and blood catecholamines in many human and animal tissues. In order to better understand the molecular processes that underlie this phenomenon we examined the effect of hypobaric hypoxia (290 mm Hg, pO2 = 40 mM Hg) on the--beta-adrenoreceptor (beta-AR) density and the activity of adenylate cyclase (AC) and phosphoinositide turnover (PI-turnover) in cultures of human pulmonary artery and umbilical vein cells. We discovered that 30 min of hypobaric hypoxia increased basal levels of inositol mono-, bis- and tris-phosphate, products of PI-turnover in endothelial cells (EC). After 60 min of hypoxia their content amounted to 250-300% of the basal level. Desensitization of PI-turnover to histamine stimulation in EC was observed after 60 min of hypoxia. Basal and isoproterenol (beta-AR-agonist)-stimulated AC activities therewith were markedly reduced. beta-AR-density was decreased in EC membranes after 2-3 hrs of hypoxia. Similar desensitization of beta-AR and AC occurred after 1-2 hrs treatment of EC with histamine and platelet activating factor (stimulators of PI-turnover) and with phorbol myristate acetate (PK C activator). Neither hyproxia nor phorbol myristate acetate influenced beta-AR density or AC activity in protein kinase C-deficient EC (72 hrs treatment with phorbol myristate acetate). The data suggest that hypoxia-induced desensitization of beta-AR and AC in endothelial cells is mediated via hypozia-stimulated turnover and subsequent protein kinase C activation.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D003470:Culture Media; D007295:Inositol Phosphates; D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; D010100:Oxygen