title: Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction.
abstract: BACKGROUND
  The core region of a myocardial infarction is notoriously unsupportive of cardiomyocyte survival. However, there has been less investigation of the potentially beneficial spontaneous recruitment of endogenous bone marrow progenitor cells (BMPCs) within infarcted areas. In the current study we examined the role of tissue oxygenation and derived toxic species in the control of BMPC engraftment during postinfarction heart remodeling.
  
  
  RESULTS
  For assessment of cellular origin, local oxygenation, redox status, and fate of cells in the infarcted region, myocardial infarction in mice with or without LacZ(+) bone marrow transplantation was induced by coronary ligation. Sham-operated mice served as controls. After 1 week, LacZ(+) BMPC-derived cells were found inhomogeneously distributed into the infarct zone, with a lower density at its core. Electron paramagnetic resonance (EPR) oximetry showed that pO2 in the infarct recovered starting on day 2 post-myocardial infarction, concomitant with wall thinning and erythrocytes percolating through muscle microruptures. Paralleling this reoxygenation, increased generation of reactive oxygen/nitrogen species was detected at the infarct core. This process delineated a zone of diminished BMPC engraftment, and at 1 week infiltrating cells displayed immunoreactive 3-nitrotyrosine and apoptosis. In vivo treatment with a superoxide dismutase mimetic significantly reduced reactive oxygen species formation and amplified BMPC accumulation. This treatment also salvaged wall thickness by 43% and left ventricular ejection fraction by 27%, with significantly increased animal survival.
  
  
  CONCLUSIONS
  BMPC engraftment in the infarct inversely mirrored the distribution of reactive oxygen/nitrogen species. Antioxidant treatment resulted in increased numbers of engrafted BMPCs, provided functional protection to the heart, and decreased the incidence of myocardial rupture and death.
authors.affiliation: Department of Internal Medicine/Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH.
authors.forename: Nicanor I
authors.initials: NI
authors.lastname: Moldovan
authors.forename: Mirela
authors.initials: M
authors.lastname: Anghelina
authors.forename: Saradhadevi
authors.initials: S
authors.lastname: Varadharaj
authors.forename: Omer I
authors.initials: OI
authors.lastname: Butt
authors.forename: Tiangshen
authors.initials: T
authors.lastname: Wang
authors.forename: Fuchun
authors.initials: F
authors.lastname: Yang
authors.forename: Leni
authors.initials: L
authors.lastname: Moldovan
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002465:Cell Movement; D004195:Disease Models, Animal; D007763:Lac Operon; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000975:Antioxidants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C002744:3-nitrotyrosine; D014443:Tyrosine
keywords: antioxidants; myocardial infarction; reactive oxygen/nitrogen species; stem/progenitor cells; ventricular rupture