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- Title
Dual roles of tumor necrosis factor-a receptor-1 in a mouse model of hindlimb ischemia.
- Authors
Jun Jiang; Jianan Wang; Changling Li; Shan Ping Yu; Ling Wei
- Abstract
Signals in the tumor necrosis factor α (TNF-α) pathway are upregulated after ischemia, yet its role in peripheral ischemia remains unclear. We investigated the effect of TNF-α receptor 1 (TNFR-1) in acute limb ischemia of TNFR-1 knockout (TNFR-1-/-) and wild type (WT, TNFR-1+/+) mice. Laser Doppler scanning showed that although pre-ischemia blood flow levels were similar in these mice, the limb reperfusion after ischemia was significantly higher in TNFR-1-/- mice 1-7 days after injury. Consistently, fewer TUNEL-positive cells, less DNA fragmentation, and a lower ischemic score were detected in the TNFR-1-/- group when compared to WT controls. Western blot analysis revealed less expression of pro-apoptotic markers Bax and cleaved caspase-3 in TNFR-1-/- mice 1 day after ischemia, supporting the hypothesis that the absence of TNFR-1 results in a reduction of apoptosis. The rate of postischemia amputation was 50% in WT mice versus 0% in TNFR-1-/- mice. However, immunohistochemical co-staining of microvessel marker CD31 and cellular proliferation marker BrdU 21 days after ischemia showed an impaired angiogenic activity in the TNFR-1-/- mice. These data were supported by Western blot analysis, which indicated a decreased expression of angiopoietin-1 (Ang-1) and its receptor Tie-2 in TNFR-1-/- mice. Our results suggest that a deficiency in TNFR-1 prevents the activation of death-related proteins downstream to TNF-α and attenuates apoptosis in acute limb ischemia, but the lack of TNFR-1 signaling hinders the belated angiogenesis mediated by the Ang-1/Tie-2 pathway.
- Subjects
TUMOR necrosis factors; GROWTH factors; HINDLIMB; ISCHEMIA; BLOOD flow; LABORATORY mice
- Publication
Vascular Medicine, 2009, Vol 14, Issue 1, p37
- ISSN
1358-863X
- Publication type
Article
- DOI
10.1177/1358863X08098143