Involvement of protein kinase C in hypoxia-induced desensitization of the beta-adrenergic system in human endothelial cells.
In order to better understand the mechanisms whereby oxygen deficiency promotes blunting of the endothelial beta-adrenergic receptor (beta-AR) system we examined the effects of hypoxia on beta-AR, adenylate cyclase (AC) activity and phosphoinositide turnover in cultures of human pulmonary artery and umbilical vein endothelial cells. 1 hr of hypobaric hypoxia (290 mm Hg) increased basal levels of inositol mono-, bis-, and tris-phosphate to those following histamine stimulation under normoxia. Basal and isoproterenol-stimulated AC activities were lowered after 1 hr of hypoxia. beta-AR density was decreased after 2-3 hrs of hypoxia and after treatment of EC with histamine, platelet activating factor or phorbol myristate acetate (PMA). In protein-kinase C (PK-C)-downregulated EC, neither hypoxia nor PMA influenced beta-AR density or AC activity. Hypoxia-induced desensitization of beta-AR signal transduction in EC may involve hypoxia-stimulated phosphoinositide turnover and subsequent PK-C activation.
Resink
T
T
Department of Research, Basel University Hospital, Switzerland.
Buravkova
L
L
Mirzapoyazova
T
T
Köhler
E
E
Erne
P
P
Tkachuk
V
V
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D010716:Phosphatidylinositols; D010972:Platelet Activating Factor; D011943:Receptors, Adrenergic, beta; D006632:Histamine; D011493:Protein Kinase C; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate