Abstract 3644: Loss of Novel Metabolic Sensor, Redox Factor-1, Impairs HIF-1a-Dependent Revascularization
Background: Ischemia is a leading cause of morbidity and mortality in the diabetic population. Impaired revascularization in response to ischemia has been well-characterized in both human diabetic cohorts and pre-clinical diabetic models. However, the mechanisms underlying the decreased revascularization in the diabetic population have not been elucidated. Diabetes induces a metabolic shift in the cellular redox state. We hypothesized that this shift resulted in a loss of a metabolic-sensor, redox factor -1 (Ref-1). Ref-1 is a multi-acting factor that senses redox balance, promotes DNA repair, and stimulates activity of the hypoxia inducible factor 1 alpha (HIF-1a) signaling pathway. Thus, we postulated that impaired revascularization in a pre-clinical model of diabetes was mediated through a loss of the Ref-1/HIF-1 signaling axis.
Methods & Results: Peripheral ischemia was induced in adult male C57BL6 mice and revascularization scored via vessel counts in the gastrocnemius muscle 14 days post ligation. The ischemic model of femoral artery ligation was characterized by 31P magnetic resonance spectroscopy. A sharp decline in the PCr/ATP and PCr/Pi ratios was evident at 1 day post ligation, followed by recovery at 14 days. A decrease in the number of vessels was found in streptozotocin-induced diabetic mice (n=4) compared to non-diabetic mice (n=10) 14 days post ligation (p < 0.02). This coincided with a significant impairment in HIF-1a translocation to the nucleus. As hypothesized, Ref-1 protein was lower in diabetic muscle (p=0.014). To test if loss of Ref-1 was sufficient to impair revascularization, peripheral ischemia was induced in Ref-1 +/− mice. Ref-1 +/− mice (n=8) exhibited a marked decline in revascularization compared to WT (n=10) (p<0.005). The decline in revascularization was coupled with impaired HIF-1a nuclear translocation.
Conclusion: Loss of Ref-1 impairs a HIF-1a mediated revascularization process following ischemia. These findings suggest that Ref-1 may serve as a critical metabolic sensor transducing changes in the redox microenvironment to the process of revascularization under ischemic conditions.