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- W2338462517 abstract "Heart disease is already the leading cause of death in the United States. People over 65 years of age are the fastest growing age group, and the incidence of heart failure is expected to increase further in the coming decades. We have previously demonstrated that upregulation of ribonucleotide reductase (RNR) in cardiomyocytes results in an elevation in the cytosolic concentration of 2-deoxy-ATP (dATP) and subsequent increase in contractility. For this approach to be an effective therapeutic option for treatment of heart failure we need to determine whether elevated cardiac dATP can be maintained long term and that it does not compromise cardiomyoctye metabolism.We found that dADP-dependent respiration of cardiac mitochondria was depressed when compared to ADP-dependent respiration, and higher concentrations of dADP are necessary to stimulate respiration. Despite this, physiological and even super-physiological (2% and 10% of adenonucleotides, respectively) dADP/ADP ratios elicited the same magnitude of respiration as 100% ADP. In addition, hearts from transgenic mice that overexpress RNR have the same maximum mitochondrial respiratory capacity as wild-type controls. We have demonstrated that the creatine phosphate/creatine phosphokinase system can phosphorylate dADP in solution, which we believe to be the predominant pathway by which dATP is produced in vivo. RNR-TG hearts showed no increase in the ratio of mitochondrial to nuclear DNA, but had slightly elevated mitochondrial volume as determined by citrate synthase activity. This may prove protective during ischemic events and prevent the shift towards a more glycolytic metabolic profile seen during cardiac stress.These data suggest that cardiomyocytes can generate dATP from dADP through the same metabolic pathways as ATP, levels of dADP associated with upregulation of RNR do not alter the cell's ability to synthesize ATP, and that elevated RNR may impart a cardioprotective effect during ischemic events." @default.
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- W2338462517 date "2016-02-01" @default.
- W2338462517 modified "2023-09-29" @default.
- W2338462517 title "Ribonucleotide Reductase Overexpression does not Alter Cardiomyocyte Mitochondrial Respiration" @default.
- W2338462517 doi "https://doi.org/10.1016/j.bpj.2015.11.791" @default.
- W2338462517 hasPublicationYear "2016" @default.
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