p66ShcA Modulates Tissue Response to Hindlimb Ischemia

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Oxidative stress plays a pivotal role in ischemia and ischemia/reperfusion injury. Because p66ShcA-null (p66ShcA−/−) 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 p66ShcA−/− 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.


p66ShcA 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.

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