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(Circulation. 2004;109:2917-2923.)
© 2004 American Heart Association, Inc.

Basic Science Reports

p66^ShcA Modulates Tissue Response to Hindlimb Ischemia

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

From Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata–IRCCS, Rome (F.M, P.F., A.M., M.C.C.); Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino–IRCCS, Milan (G.Z., A.D.); Dipartimento di Chirurgia Cardiovascolare, Centro Cardiologico Monzino–IRCCS, Milan (P.B.); and Istituto Europeo di Oncologia, Milan (I.M.-P., M.G., P.G.P.), Italy.

Correspondence to Fabio Martelli, PhD, Laboratorio Patologia Vascolare, Istituto Dermopatico dell’Immacolata–IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy. E-mail f.martelli{at}idi.it

Received July 31, 2003; de novo received January 28, 2004; revision received March 2, 2004; accepted March 4, 2004.

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.

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 p66^ShcA wild-type (p66^ShcAwt) and p66^ShcA–/– mice. However, significant differences in tissue damage were found: p66^ShcAwt 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.

Key Words: ischemia • reperfusion • free radicals • apoptosis • muscles

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