Date on Master's Thesis/Doctoral Dissertation

8-2016

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Bhatnagar, Aruni

Committee Co-Chair (if applicable)

Baba, Shahid

Committee Member

Baba, Shahid

Committee Member

Clark, Barbara

Committee Member

Cole, Marsha

Committee Member

Cheng, Alan

Author's Keywords

carnosine; angiogenesis; arteriogenesis; hypoxia; hindlimb; ischemia

Abstract

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 (HIF1-α) plays an important role in recovery from murine hindlimb ischemia (HLI). HIF1-α is regulated by oxygen dependent prolyl hydroxylases (PHDs). Previous studies have shown that inhibition of PHDs by metal quenchers and viral delivery of HIF1-α improves blood flow to the ischemic limb. However, clinical trials with these therapies are largely negative partly because they do not address the underlying chronic oxidative stress. Based on recent observations that endogenous histidyl dipeptides such as carnosine can chelate metals and quench reactive carbonyls, we hypothesize that supplementation of carnosine can promote revascularization to enhance wound healing through aldehyde quenching and metal chelation. C57BL/6 mice were subjected to hindlimb ischemia (HLI) surgery by ligating the femoral artery and vein and supplemented with carnosine (1g/L) for 21 days. Laser Doppler analysis showed that blood flow in carnosine treated mice was significantly increased (31±2%) compared with the non-treated mice (20±2%) after 14 and 21 days (carnosine 50±6% vs non-treated 28±4%; p

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