TY - JOUR
T1 - p66ShcA modulates tissue response to hindlimb ischemia
AU - Zaccagnini, Germana
AU - Martelli, Fabio
AU - Fasanaro, Pasquale
AU - Magenta, Alessandra
AU - Gaetano, Carlo
AU - Di Carlo, Anna
AU - Biglioli, Paolo
AU - Giorgio, Marco
AU - Martin-Padura, Ines
AU - Pelicci, Pier Giuseppe
AU - Capogrossi, Maurizio C.
PY - 2004/6/15
Y1 - 2004/6/15
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Free radicals
KW - Ischemia
KW - Muscles
KW - Reperfusion
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U2 - 10.1161/01.CIR.0000129309.58874.0F
DO - 10.1161/01.CIR.0000129309.58874.0F
M3 - Article
C2 - 15173034
AN - SCOPUS:16544365687
VL - 109
SP - 2917
EP - 2923
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 23
ER -