Abstract 20151: Supplementation of Carnosine Improves Wound Healing Responses
Introduction: Critical Limb ischemia (CLI) is a serious manifestation of peripheral artery disease. Advanced CLI patients are poor candidates for vascular surgeries. Numerous studies have shown that Hypoxia inducible factor 1α plays an important role in recovery. HIF1-α is regulated by oxygen dependent prolyl hydroxylases (PHDs). Previous studies had shown that inhibition of PHDs by metal quenchers and viral delivery of HIF1-α iimproves blood flow to the ischemic limb. However clinical trials with these therapies were largely negative.
Hypothesis: Based on recent observations that endogenous histidyl dipeptides such as carnosine a food constituent can quench metals we hypothesize that supplementation of carnosine can inhibit PHDs, stabilize HIF1-α and attenuate ischemic injury.
Methods: C57BL/6J mice were subjected to hindlimb ischemia (HLI) surgery by ligating the femoral artery and vein and supplemented with carnosine (1g/L) for 21 days.
Results: Laser Doppler analysis showed that blood flow in the carnosine treated was significantly increased (31±2%) compared with the non-treated (20±2%) after 14 and 21 days (carnosine 50±6% vs non-treated 28±4%; p<0.05) of HLI surgery. Vascular density measured by 3D-microCT was significantly enhanced by carnosine treatment compared with non-treated HLI mice. Similarly muscle regeneration and iso-lectin staining in the carnosine treated was significantly increased compared to the non-treated mice. The mobilization of endothelial progenitor cells (Flk+/Sca+) in the blood and VEGF expression in the ischemic limb was significantly increased by carnosine supplementation. Levels of carnosine in the ischemic muscle were increased 2 fold compared with non-treated HLI mice. Pre-treatment of C2C12 cells with carnosine and its analogue methyl carcinine that lacks the ability to quench metals showed increased HIF1-α nuclear translocation and VEGF secretion in hypoxic carnosine treated cells compared with carcinine treated hypoxic cells.
Conclusions: Collectively our results demonstrate that carnosine treatment improves blood flow by increasing HIF1-α stabilization and EPC mobilization and thus can be used as a safe therapeutic intervention for CLI patients
- Peripheral artery disease (PAD)
- Endothelial progenitor cell
- Vascular development
Author Disclosures: A. Boakye: None. L. Guo: None. J. Thomas: None. D. conklin: None. A. Bhatnagar: None. S.P. Baba: None.
- © 2016 by American Heart Association, Inc.