Journal article
Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury
Journal of the American Heart Association, Vol.9(12), pp.e015222-e015222
06/16/2020
DOI: 10.1161/jaha.119.015222
PMCID: PMC7429021
PMID: 32515247
Abstract
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
-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
-2-nonenal-protein adducts in ischemic hearts and delayed acrolein or 4-hydroxy
-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.
Details
- Title: Subtitle
- Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury
- Creators
- Jingjing Zhao - University of LouisvilleDaniel J Conklin - University of LouisvilleYiru Guo - University of LouisvilleXiang Zhang - University of LouisvilleDetlef Obal - Stanford UniversityLuping Guo - University of LouisvilleGanapathy Jagatheesan - University of LouisvilleKartik Katragadda - University of LouisvilleLiqing He - University of LouisvilleXinmin Yin - University of LouisvilleMd Aminul Islam Prodhan - University of LouisvilleJasmit Shah - Aga Khan University NairobiDavid Hoetker - University of LouisvilleAmit Kumar - University of Colorado DenverVijay Kumar - University of Colorado DenverMichael F Wempe - University of Colorado DenverAruni Bhatnagar - University of LouisvilleShahid P Baba - University of Louisville
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.9(12), pp.e015222-e015222
- DOI
- 10.1161/jaha.119.015222
- PMID
- 32515247
- PMCID
- PMC7429021
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Grant note
- P30 GM127607 / NIGMS NIH HHS R01 HL055477 / NHLBI NIH HHS R01 HL122581 / NHLBI NIH HHS
- Language
- English
- Date published
- 06/16/2020
- Academic Unit
- Anesthesia
- Record Identifier
- 9984696722902771
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