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Dual roles of tumor necrosis factor- receptor-1 in a mouse model of hindlimb ischemia

Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

Jianan Wang

Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China

Changling Li

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA; Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China lwei7{at}emory.edu

Shan Ping Yu

Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA

Ling Wei

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA lwei7{at}emory.edu

Abstract

Signals in the tumor necrosis factor (TNF-) pathway are upregulated after ischemia, yet its role in peripheral ischemia remains unclear. We investigated the effect of TNF- 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 post-ischemia 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- 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.

Key Words: angiogenesis • apoptosis • peripheral ischemia • TNFR-1

Vascular Medicine, Vol. 14, No. 1, 37-46 (2009)
DOI: 10.1177/1358863X08098143


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