Abstract 14774: Rescue of Diabetes-related Impairment of Ischemia-mediated Neovascularization With Fenofibrate Treatment:
Fascinating stuff from our colleagues Tony Keech, et al from down under. Enjoy.
Abstract 14774: Rescue of Diabetes-related Impairment of Ischemia-mediated Neovascularization With Fenofibrate Treatment
- Kushwin Rajamani1;
- Jun Yuan2;
- Laura Lecce3;
- Alicia Jenkins1;
- Anthony Keech1;
- Martin Ng4
1Public Health, NHMRC Clinical Trials Cntr, Sydney, NSW, Australia
2Translational health, Heart Rsch Institute, NSW, Australia
3Translational Rsch, Heart Rsch Insitute, NSW, Australia
4Translational Rsch, Heart Rsch Institute, Sydney, NSW, Australia
Background: Fenofibrate, a PPARα agonist, reduced amputation events in the Fenofibrate Intervention and Event Lowering in Diabetes study among 9795 patients, the mechanisms of which are unknown. We hypothesised that fenofibrate may attenuate diabetes-related impairment in ischemia-mediated neovascularization.
Methods: Hindlimb ischemia was induced in a murine model of streptozotocin induced diabetes mellitus (DM) in wildtype and PPARα receptor knockout mice (KO) with/without fenofibrate (30mg/kg/day in high fat diet). Ischemic recovery was assessed by laser doppler, foot movement and capillary density analysis. Key angiogenic events (tubulogenesis) and expression of thioredoxin-interacting protein (TXNIP) mRNA and protein following normal and high glucose (5 vs 25mM glucose) environments were determined in cultured endothelial cells (ECs), with/without selective PPARα receptor antagonist (10μM MK886) and agonist (10μM WY14643).
Results: DM profoundly impaired blood flow recovery following hindlimb ischemia (0.51±0.04[n=5] vs 0.34±0.03[n=5];p<0.001). Fenofibrate (FF) restored DM-related impairment in blood flow recovery (0.53±0.04[n=5] vs 0.34±0.03[n=5];p<0.01), capillary density (1.48±0.03 vs1.20±0.04;p<0.01), foot movement scores to levels of non-diabetic controls. Similar findings for fenofibrate were observed in diabetic PPARα KO mice. In vitro, fenofibric acid (FA) rescued hyperglycemia-induced impairment in EC tubulogenesis (87.8 vs 58.3% of control;p<0.05) by a PPARα-independent mechanism. FA prevented hyperglycemia-induced overexpression of TXNIP (mRNA: 1.20±0.16 vs 1.84±0.28 folds of control;p<0.01) an exquisitely glucose-sensitive regulator of angiogenesis, in a PPARα-independent manner. Furthermore, overexpression of TXNIP abrogated the protective effects of FA.
Conclusions: Fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis via a largely PPARα-independent mechanism. Improved neovascularization may therefore explain in part the reduced amputations seen with fenofibrate in type 2 diabetes. These findings provide a novel mechanistic understanding for fenofibrate action and may provide a platform for new drug targets.