p66ShcA modulates tissue response to hindlimb ischemia

Germana Zaccagnini, Fabio Martelli, Pasquale Fasanaro, Alessandra Magenta, Carlo Gaetano, Anna Di Carlo, Paolo Biglioli, Marco Giorgio, Ines Martin-Padura, Pier Giuseppe Pelicci, Maurizio C. Capogrossi

Research output: Contribution to journalArticlepeer-review

Abstract

Background-Oxidative stress plays a pivotal role in ischemia and ischemia/reperfusion injury. Because p66ShcA-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 p66ShcA-/- mice. Methods and 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 p66ShcA wild-type (p66ShcAwt) and p66ShcA-/- mice. However, significant differences in tissue damage were found: p66ShcAwt mice displayed marked capillary density decrease and muscle fiber necrosis. In contrast, in p66ShcA-/- 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 p66ShcA-/- mice were resistant to apoptosis induced by simulated ischemia in vitro. Lower apoptosis levels after ischemia in p66ShcA-/- 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 p66ShcA as a potential therapeutic target for prevention and treatment of ischemic tissue damage.

Original languageEnglish
Pages (from-to)2917-2923
Number of pages7
JournalCirculation
Volume109
Issue number23
DOIs
Publication statusPublished - Jun 15 2004

Keywords

  • Apoptosis
  • Free radicals
  • Ischemia
  • Muscles
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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