Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury.

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 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.

• Authors: Jingjing Zhao, Daniel J Conklin, Yiru Guo, Xiang Zhang, Detlef Obal, Luping Guo, Ganapathy Jagatheesan, Kartik Katragadda, Liqing He, Xinmin Yin, Md Aminul Islam Prodhan, Jasmit Shah, David Hoetker, Amit Kumar, Vijay Kumar, Michael F Wempe, Aruni Bhatnagar, Shahid P Baba
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 9 Issue 12 Pg. e015222 (06 16 2020) ISSN: 2047-9980 [Electronic] England
• PMID: 32515247 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aldehydes
• beta-Alanine
• Acrolein
• Carnosine
• Adenosine Triphosphate
• Peptide Synthases
• carnosine synthetase
• 4-hydroxy-2-nonenal

Topics

• Acrolein (metabolism)
• Adenosine Triphosphate (metabolism)
• Aldehydes (metabolism)
• Animals
• Carnosine (metabolism, pharmacology)
• Cell Hypoxia
• Disease Models, Animal
• Energy Metabolism
• Hydrogen-Ion Concentration
• Lipid Peroxidation (drug effects)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardial Infarction (enzymology, genetics, pathology, prevention & control)
• Myocardial Reperfusion Injury (enzymology, genetics, pathology, prevention & control)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Peptide Synthases (genetics, metabolism)
• Up-Regulation
• beta-Alanine (pharmacology)