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

Autor: Yiru Guo, Michael F. Wempe, Liqing He, Xiang Zhang, Ganapathy Jagatheesan, Aruni Bhatnagar, Amit Kumar, Vijay Kumar, Shahid P Baba, Kartik Katragadda, Aminul Islam Prodhan, Xinmin Yin, Jasmit Shah, Jingjing Zhao, David Hoetker, Daniel J. Conklin, Luping Guo, Detlef Obal
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Myocardial Infarction
Carnosine
030204 cardiovascular system & hematology
Pharmacology
Molecular Cardiology
Lipid peroxidation
chemistry.chemical_compound
0302 clinical medicine
Adenosine Triphosphate
Ischemia
Medicine
Glycolysis
Myocytes
Cardiac
Carnosine synthase
Acrolein
Peptide Synthases
Original Research
0303 health sciences
biology
Hydrogen-Ion Concentration
Cell Hypoxia
Up-Regulation
Cardiology and Cardiovascular Medicine
anserine
Intracellular pH
Anserine
intracellular pH
Mice
Transgenic
Myocardial Reperfusion Injury
03 medical and health sciences
carnosine synthase
ischemia reperfusion
Animals
balenine
030304 developmental biology
Aldehydes
business.industry
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Metabolism
chemistry
biology.protein
beta-Alanine
Lipid Peroxidation
business
Oxidant Stress
Energy Metabolism
Reperfusion injury
Basic Science Research
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: 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 ATPGD 1 increased myocardial histidyl dipeptides levels and protected the heart from I/R injury. Isolated cardiac myocytes from ATPGD 1‐transgenic hearts were protected against hypoxia reoxygenation injury. The overexpression of ATPGD 1 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 ATPGD 1‐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: OpenAIRE
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