title: p66ShcA modulates tissue response to hindlimb ischemia.
abstract: BACKGROUND
  Oxidative stress plays a pivotal role in ischemia and ischemia/reperfusion injury. Because p66(ShcA)-null (p66(ShcA)-/-) mice exhibit both lower levels of intracellular reactive oxygen species and increased resistance to cell death induced by oxidative stress, we investigated whether tissue damage that follows acute ischemia or ischemia/reperfusion was altered in p66(ShcA)-/- mice.
  
  
  RESULTS
  Unilateral hindlimb ischemia was induced by femoral artery dissection, and ischemia/reperfusion was induced with an elastic tourniquet. Both procedures caused similar changes in blood perfusion in p66(ShcA) wild-type (p66(ShcA)wt) and p66(ShcA)-/- mice. However, significant differences in tissue damage were found: p66(ShcA)wt mice displayed marked capillary density decrease and muscle fiber necrosis. In contrast, in p66(ShcA)-/- mice, minimal capillary density decrease and myofiber death were present. When apoptosis after ischemia was assayed, significantly lower levels of apoptotic endothelial cells and myofibers were found in p66(ShcA)-/- mice. In agreement with these data, both satellite muscle cells and endothelial cells isolated from p66(ShcA)-/- mice were resistant to apoptosis induced by simulated ischemia in vitro. Lower apoptosis levels after ischemia in p66(ShcA)-/- cells correlated with decreased levels of oxidative stress both in vivo and in vitro.
  
  
  CONCLUSIONS
  p66(ShcA) plays a crucial role in the cell death pathways activated by acute ischemia and ischemia/reperfusion, indicating p66(ShcA) as a potential therapeutic target for prevention and treatment of ischemic tissue damage.
authors.affiliation: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Germana
authors.initials: G
authors.lastname: Zaccagnini
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fasanaro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Magenta
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.forename: Anna
authors.initials: A
authors.lastname: Di Carlo
authors.forename: Paolo
authors.initials: P
authors.lastname: Biglioli
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Ines
authors.initials: I
authors.lastname: Martin-Padura
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000503:physiopathology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D017392:Thiobarbituric Acid Reactive Substances; D042461:Vascular Endothelial Growth Factor A