Abstract
Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It improves angiogenesis and tissue perfusion in ischemic skeletal muscle. In the present study, we tested the hypothesis that ischemic postconditioning is effective for salvaging ischemic skeletal muscle resulting from limb ischemia-reperfusion injury, and that the mechanism involves expression of HIF-1α. Wistar rats were randomly divided into three groups (n=36 each): sham-operated (group S), hindlimb ischemia-reperfusion (group IR), and ischemic postconditioning (group IPO). Each group was divided into subgroups (n=6) according to reperfusion time: immediate (0 h, T0), 1 h (T1), 3 h (T3), 6 h (T6), 12 h (T12), and 24 h (T24). In the IPO group, three cycles of 30-s reperfusion and 30-s femoral aortic reocclusion were carried out before reperfusion. At all reperfusion times (T0-T24), serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities, as well as interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF-α) concentrations, were measured in rats after they were killed. Histological and immunohistochemical methods were used to assess the skeletal muscle damage and HIF-1α expression in skeletal muscle ischemia. In groups IR and IPO, serum LDH and CK activities and TNF-α, IL-6, and IL-10 concentrations were all significantly increased compared to group S, and HIF-1α expression was up-regulated (P<0.05 or P<0.01). In group IPO, serum LDH and CK activities and TNF-α and IL-6 concentrations were significantly decreased, IL-10 concentration was increased, HlF-1α expression was down-regulated (P<0.05 or P<0.01), and the pathological changes were reduced compared to group IR. The present study suggests that ischemic postconditioning can reduce skeletal muscle damage caused by limb ischemia-reperfusion and that its mechanisms may be related to the involvement of HlF-1α in the limb ischemia-reperfusion injury-triggered inflammatory response.
Highlights
Ischemia-reperfusion (IR) injury occurs when tissue is reperfused following a period of ischemia, and results from acute inflammation involving various mechanisms
Quantitative analysis showed significantly increased scores in the IR group compared with the S group and decreased scores in the ischemic postconditioning (IPO) group compared with the IR group (P,0.01, Figure 2D)
We evaluated whether the effect of anti-tumor necrosis factor-a (TNF-a), antiIL-6, or anti-IL-10 was correlated with inhibition or promotion of Hypoxia-inducible factor-1a (HIF-1a) expression in skeletal muscle injury induced by limb IR
Summary
Ischemia-reperfusion (IR) injury occurs when tissue is reperfused following a period of ischemia, and results from acute inflammation involving various mechanisms. The effects of lower extremity IR occur across a spectrum ranging from mild injury with no lasting sequelae to a systemic response with multi-organ injury This process may give rise to generalized inflammation with activation of different immune cells, release of a vast number of inflammatory mediators, reactive free radicals, and vasoactive substances [1,2]. To our knowledge, no investigations have yet been made into the problem of inflammation and its effect on angiogenesis in skeletal muscle ischemia from lower limb IR injury. The present study was performed to determine the role of ischemic postconditioning in skeletal muscle ischemia induced by limb ischemiareperfusion, and whether its mechanism involves HIF-1a expression
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