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- Title
Fenofibrate Rescues Diabetes-Related Impairment of Ischemia-Mediated Angiogenesis by PPARα-Independent Modulation of Thioredoxin-Interacting Protein.
- Authors
King, Emily J.; Lecce, Laura; Simpson, Philippa J. L.; Jun Yuan; Yuen Ting Lam; Tan, Joanne T. M.; Bursill, Christina A.; Rajamani, Kushwin; Ng, Martin K. C.; Jenkins, Alicia J.; Keech, Anthony C.; Solly, Emma L.; Yuan, Jun; Lam, Yuen Ting
- Abstract
Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, reduces lower limb amputations in patients with type 2 diabetes. 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 PPARα-knockout mice, indicating that these fenofibrate effects are largely PPARα independent. In vitro, fenofibric acid (FFA) rescued high glucose-induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPARα-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose-induced 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-impaired 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 PPARα-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate.
- Subjects
THIOREDOXIN-interacting protein; FENOFIBRATE; VASCULAR endothelial growth factors; LEG amputation; PEROXISOME proliferator-activated receptors
- Publication
Diabetes, 2019, Vol 68, Issue 5, p1040
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-0926