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The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPAR\u03b1-knockout mice, indicating that these fenofibrate effects are largely PPAR\u03b1 independent. In vitro, fenofibric acid (FFA) rescued high glucose\u2013induced (25 mmol\/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPAR\u03b1-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose\u2013induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetes-related impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose\u2013impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis, in large part, by PPAR\u03b1-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate.<\/jats:p>","DOI":"10.2337\/db17-0926","type":"journal-article","created":{"date-parts":[[2019,2,15]],"date-time":"2019-02-15T01:15:46Z","timestamp":1550193346000},"page":"1040-1053","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":27,"title":["Fenofibrate Rescues Diabetes-Related Impairment of Ischemia-Mediated Angiogenesis by PPAR\u03b1-Independent Modulation of Thioredoxin-Interacting Protein"],"prefix":"10.2337","volume":"68","author":[{"given":"Jun","family":"Yuan","sequence":"first","affiliation":[{"name":"Heart Research Institute, Newtown, New South Wales, Australia"},{"name":"Sydney Medical School, The University of Sydney, Sydney, New South Wales, 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