Metabolism, Oxygen, Ischaemia and ProtectionP343Mitochondrial respiration is reduced after myocardial infarction in chronic ischemic myocardium as well as in the remote non-ischemic region

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Abstract

Background

Remodeling after myocardial infarction (MI) is associated with alterations in metabolism and energetics. We investigated whether changes in mitochondrial respiration were present after MI in regions with chronic ischemia as well as in the remote non-ischemic myocardium.

Methods

A copper-coated stent was inserted in the left-anterior descending of domestic pigs inducing a small MI in the anterior wall. Cardiac myocytes were isolated from the area adjacent to the MI (MI-adj) and the remote area (remote-MI) (Nanimals=5). Data were compared to myocytes isolated from the two matching regions from SHAM-operated animals (Nanimals=5). Cells were seeded at a density of 2000 cells per well. Oxygen consumption rates in permeabilized cardiomyocytes were measured using a Seahorse Bioscience XF24 Extracellular Flux Analyzer.

Results

Basal oxygen consumption rate was significantly lower in MI-adj and in remote-MI compared to SHAM (-28% and -40 % respectively vs. SHAM, P < 0.05). Maximal oxygen consumption rate (measured in the presence of 2 mM ADP) was reduced in MI-adj (419 ± 179 pmol/min in MI-adj vs.1109 ± 94 pmol/min in SHAM, P < 0.05) as well as in the remote area (411 ± 168 pmol/min vs. 989 ± 90 pmol/min in SHAM, P < 0.05). Coupling between respiration and phosphorylation, estimated as a ratio between maximal rate under ADP over basal rate, was comparable within the groups. Maximal oxidative capacity either from complex I (using glutamate / malate as substrate) and from complex II (using succinate as substrate) was reduced to the same extend, in both MI-adj and in remote-MI (- 35 % in both groups vs. SHAM for complex I, -40 % in both groups vs. SHAM for complex II, P < 0.05). Respiration through complex III, measured as the antimycin-sensitive respiration, was unchanged. In the presence of different substrates, oxygen consumption rates were significantly lower in MI-adj and remote-MI compared to the matched SHAM, either with octoanoate, pyruvate or glutamate. Normalization to maximal oxygen consumption rate revealed that in SHAM and in remote-MI, both octanoate and pyruvate were used without any preference. In MI-adj, however, respiration with octanoate was reduced by 17% compared to SHAM (P < 0.05) while respiration with pyruvate was maintained. Relative use of glutamate was comparable within the groups.

Conclusion

Myocytes from ischemic regions as well as from the remote non-ischemic area have a reduced mitochondrial oxidative capacity and a reduced function of the respiratory chain complexes I and II. A switch in substrate preference towards carbohydrates was observed in the ischemic area only.

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