Fenofibrate Rescues Diabetes-Related Impairment of Ischemia-Mediated Angiogenesis by PPARa-Independent Modulation of Thioredoxin Interacting Protein

Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARa) agonist, reduces lower limb amputations in patients with type 2 diabetes mellitus. The mechanism is, however, unknown. Here 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 (VEGF) signaling to non-diabetic levels in both wildtype and PPARa-knockout mice, indicating that these fenofibrate effects are largely PPARa-independent. In vitro, fenofibric acid (FFA) rescued high glucose (25 mM)-induced impairment of endothelial cell migration, tubulogenesis and survival, in a PPARa-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 PPARa-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in diabetic patients treated with fenofibrate.