| Autor: |
Zhao J; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., Conklin DJ; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., Guo Y; Division of Cardiovascular Medicine Department of Medicine University of Louisville KY., Zhang X; Department of Chemistry University of Louisville KY., Obal D; Department of Anesthesiology and Perioperative and Pain Medicine Stanford University Palo Alto CA., Guo L; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., Jagatheesan G; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., Katragadda K; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., He L; Department of Chemistry University of Louisville KY., Yin X; Department of Chemistry University of Louisville KY., Prodhan MAI; Department of Chemistry University of Louisville KY., Shah J; Department of Medicine The Aga Khan University Medical College Nairobi Kenya., Hoetker D; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., Kumar A; Department of Pharmaceutical Sciences University of Colorado Denver CO., Kumar V; Department of Pharmaceutical Sciences University of Colorado Denver CO., Wempe MF; Department of Pharmaceutical Sciences University of Colorado Denver CO., Bhatnagar A; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY., Baba SP; Diabetes and Obesity Center University of Louisville KY.; Christina Lee Brown Envirome Institute University of Louisville KY. |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of the American Heart Association [J Am Heart Assoc] 2020 Jun 16; Vol. 9 (12), pp. e015222. Date of Electronic Publication: 2020 Jun 09. |
| DOI: |
10.1161/JAHA.119.015222 |
| Abstrakt: |
BACKGROUND Myocardial ischemia reperfusion (I/R) injury is associated with complex pathophysiological changes characterized by pH imbalance, the accumulation of lipid peroxidation products acrolein and 4-hydroxy trans -2-nonenal, and the depletion of ATP levels. Cardioprotective interventions, designed to address individual mediators of I/R injury, have shown limited efficacy. The recently identified enzyme ATPGD1 (Carnosine Synthase), which synthesizes histidyl dipeptides such as carnosine, has the potential to counteract multiple effectors of I/R injury by buffering intracellular pH and quenching lipid peroxidation products and may protect against I/R injury . METHODS AND RESULTS We report here that β-alanine and carnosine feeding enhanced myocardial carnosine levels and protected the heart against I/R injury. Cardiospecific overexpression of ATPGD1 increased myocardial histidyl dipeptides levels and protected the heart from I/R injury. Isolated cardiac myocytes from ATPGD1-transgenic hearts were protected against hypoxia reoxygenation injury. The overexpression of ATPGD1 prevented the accumulation of acrolein and 4-hydroxy trans -2-nonenal-protein adducts in ischemic hearts and delayed acrolein or 4-hydroxy trans -2-nonenal-induced hypercontracture in isolated cardiac myocytes. Changes in the levels of ATP, high-energy phosphates, intracellular pH, and glycolysis during low-flow ischemia in the wild-type mice hearts were attenuated in the ATPGD1-transgenic hearts. Two natural dipeptide analogs (anserine and balenine) that can either quench aldehydes or buffer intracellular pH, but not both, failed to protect against I/R injury. CONCLUSIONS Either exogenous administration or enhanced endogenous formation of histidyl dipeptides prevents I/R injury by attenuating changes in intracellular pH and preventing the accumulation of lipid peroxidation derived aldehydes. |
| Databáze: |
MEDLINE |
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