title: Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models.
abstract: OBJECTIVE
  Oxidative stress is involved in the development of cardiovascular disease. There is a growing body of evidence for a crosstalk between different enzymatic sources of oxidative stress. With the present study, we sought to determine the underlying crosstalk mechanisms, the role of the mitochondrial permeability transition pore (mPTP), and its link to endothelial dysfunction.
  
  
  RESULTS
  NADPH oxidase (Nox) activation (oxidative burst and translocation of cytosolic Nox subunits) was observed in response to mitochondrial reactive oxygen species (mtROS) formation in human leukocytes. In vitro, mtROS-induced Nox activation was prevented by inhibitors of the mPTP, protein kinase C, tyrosine kinase cSrc, Nox itself, or an intracellular calcium chelator and was absent in leukocytes with p47phox deficiency (regulates Nox2) or with cyclophilin D deficiency (regulates mPTP). In contrast, the crosstalk in leukocytes was amplified by mitochondrial superoxide dismutase (type 2) (MnSOD(+/-)) deficiency. In vivo, increases in blood pressure, degree of endothelial dysfunction, endothelial nitric oxide synthase (eNOS) dysregulation/uncoupling (e.g., eNOS S-glutathionylation) or Nox activity, p47phox phosphorylation in response to angiotensin-II (AT-II) in vivo treatment, or the aging process were more pronounced in MnSOD(+/-) mice as compared with untreated controls and improved by mPTP inhibition by cyclophilin D deficiency or sanglifehrin A therapy.
  
  
  METHODS
  These results provide new mechanistic insights into what extent mtROS trigger Nox activation in phagocytes and cardiovascular tissue, leading to endothelial dysfunction.
  
  
  CONCLUSIONS
  Our data show that mtROS trigger the activation of phagocytic and cardiovascular NADPH oxidases, which may have fundamental implications for immune cell activation and development of AT-II-induced hypertension.
authors.affiliation: 1 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University , Mainz, Germany .
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steven
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Scholz
authors.forename: Steffen
authors.initials: S
authors.lastname: Daub
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Mikhed
authors.forename: Elena
authors.initials: E
authors.lastname: Zinssius
authors.forename: Michael
authors.initials: M
authors.lastname: Mader
authors.forename: Paul
authors.initials: P
authors.lastname: Stamm
authors.forename: Nicolai
authors.initials: N
authors.lastname: Treiber
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010545:Peroxides / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D010545:Peroxides; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D021983:Cyclophilins