title: Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease.
abstract: OBJECTIVE
  Angiotensin II (Ang II)-mediated induction of vascular superoxide anion formation could contribute to the development of endothelial dysfunction, hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a major endothelial source of superoxide anions. However, the molecular mechanism underlying the regulation of NAD(P)H oxidase activity in response to Ang II is not well understood.
  
  
  RESULTS
  We investigated the dose-dependent regulation of superoxide anion formation and of NAD(P)H oxidase subunit expression in response to Ang II in human endothelial cells. Ang II regulates superoxide anion formation and the limiting subunit of endothelial NAD(P)H oxidase, gp91-phox, in a dose-dependent manner via Ang II type 1 (AT1) receptor-mediated induction and Ang II type 2 receptor-mediated partial inhibition at higher Ang II concentrations. Furthermore, AT1 receptor blocker therapy before coronary bypass surgery downregulates the gp91-phox expression in internal mammary artery biopsies of patients with coronary artery disease.
  
  
  CONCLUSIONS
  Our data support a dose-dependent induction of proatherosclerotic oxidative stress in human endothelial cells in response to Ang II. The expression of NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion formation. AT1 receptor blockade has an antiatherosclerotic and antioxidative potential by the reduction of oxidative stress in the vessel wall.
authors.affiliation: Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rueckschloss
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Juergen
authors.initials: J
authors.lastname: Holtz
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D001026:Coronary Artery Bypass / Q000379:methods; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008323:Mammary Arteries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D018384:Oxidative Stress / Q000502:physiology; D011300:Preoperative Care / Q000379:methods; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects; D012189:Retrospective Studies; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D008562:Membrane Glycoproteins; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; C073402:PD 123319; D009247:NADH, NADPH Oxidoreductases; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C081643:candesartan