p66 ShcA 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. 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 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.