Work

Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion

Year: 2022

Type: article

Abstract: ABSTRACT Tissue ischemia results in intracellular pH (pH IN ) acidification, and while accumulation of metabolites such as lactate is a known driver of acidic pH IN , less is known about how acidic pH IN regulates metabolism. Furthermore, acidic extracellular (pH EX ) during early reperfusion confers cardioprotection, but how this impacts metabolism is unclear. Herein we employed LCMS based targeted metabolomics to analyze perfused mouse hearts exposed to: (i) control perfusion, (ii) hypoxia, (iii) ischemia, (iv) enforced acidic pH IN , (v) control reperfusion, and (vi) acidic pH EX (6.8) reperfusion. Surprisingly little overlap was seen between metabolic changes induced by hypoxia, ischemia, and acidic pH IN . Acidic pH IN elevated metabolites in the top half of glycolysis, and enhanced glutathione redox state. Acidic pH EX reperfusion induced substantial metabolic changes in addition to those seen in control reperfusion. This included elevated metabolites in the top half of glycolysis, prevention of purine nucleotide loss, and an enhancement in glutathione redox state. These data led to parallel hypotheses regarding potential roles for methylglyoxal inhibiting the mitochondrial permeability transition pore, and for acidic inhibition of ecto-5’-nucleotidase, as potential mediators of cardioprotection by acidic pH EX reperfusion. However, neither hypothesis was supported by subsequent experiments. In contrast, analysis of cardiac effluents revealed complex effects of pH EX on metabolite transport, suggesting that mildly acidic pH EX may protect in part by enhancing succinate release during reperfusion. Overall, each intervention had distinct and overlapping metabolic effects, suggesting acidic pH is an independent metabolic regulator regardless which side of the cell membrane it is imposed. HIGHLIGHTS Hypoxia, ischemia and acidic pH IN each induce unique cardiac metabolic profiles. Acidic pH EX at reperfusion prevents purine loss and enhances succinate release.

Source: Journal of Molecular and Cellular Cardiology

DOI: 10.1016/j.yjmcc.2022.11.008

Authors: Alexander S. Milliken, Jessica H. Ciesla, Sergiy M. Nadtochiy, Paul S. Brookes

Institutions: University of Rochester Medicine, University of Rochester

Language: English

Topic: Cardiac Ischemia and Reperfusion

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,320