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Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern.

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dc.abstract.enObjective: Dyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidaemia in cardiomyocytes collectively constitute an alternative pathway that escalates myocardial injury. Methods: Dyslipidaemic apolipoprotein E and low-density lipoprotein receptor (ApoE/LDLR) double knockout (ApoE(-/-)/LDLR-/-) and wild- type C57BL/6 (WT) mice aged six months old were studied. Cardiac injury under reduced oxygen supply was evaluated by 5 min exposure to 5% oxygen in the breathing air under electrocardiogram (ECG) recording and with the assessment of troponin I release. To address the mechanisms LC/MS was used to analyse the cardiac proteome pattern or in vivo metabolism of stable isotope-labelled substrates and HPLC was applied to measure concentrations of cardiac high-energy phosphates. Furthermore, the effect of blocking fatty acid use with ranolazine on the substrate preference and cardiac hypoxic damage was studied in ApoE(-/-)/LDLR-/- mice. Results: Hypoxia induced profound changes in ECG ST-segment and troponin I leakage in ApoE(-/-)/LDLR-/- mice but not in WT mice. The evaluation of the cardiac proteomic pattern revealed that ApoE(-/-)/LDLR-/- as compared with WT mice were characterised by coordinated increased expression of mitochondrial proteins, including enzymes of fatty acids' and branched-chain amino acids' oxidation, accompanied by decreased expression levels of glycolytic enzymes. These findings correlated with in vivo analysis, revealing a reduction in the entry of glucose and enhanced entry of leucine into the cardiac Krebs cycle, with the cardiac high-energy phosphates pool maintained. These changes were accompanied by the activation of molecular targets controlling mitochondrial metabolism. Ranolazine reversed the oxidative metabolic shift in ApoE(-/-)/LDLR-/- mice and reduced cardiac damage induced by hypoxia. Conclusions: Wesuggest a novelmechanism formyocardial injury in dyslipidaemia that is consequent to an increased reliance on oxidativemetabolismin the heart. The alterations in themetabolic pattern thatwe identified constitute an adaptive mechanism that facilitates maintenance of metabolic equilibrium and cardiac function under normoxia. However, this adaptation could account for myocardial injury even in a mild reduction of oxygen supply.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorDadlez, Michał
dc.contributor.authorChlopicki, Stefan
dc.contributor.authorSmeda, Marta
dc.contributor.authorSmolenski, Ryszard T.
dc.contributor.authorKochan, Zdzislaw
dc.contributor.authorBorkowski, Tomasz
dc.contributor.authorPrzyborowski, Kamil
dc.contributor.authorSzupryczynska, Natalia
dc.contributor.authorZabielska-Kaczorowska, Magdalena
dc.contributor.authorTyrankiewicz, Urszula
dc.contributor.authorDebski, Janusz
dc.contributor.authorOlkowicz, Mariola
dc.contributor.authorTomczyk, Marta
dc.date.accessioned2024-01-24T22:48:12Z
dc.date.available2024-01-24T22:48:12Z
dc.date.issued2021
dc.description.financePublikacja bezkosztowa
dc.description.numberbrak
dc.description.volume114
dc.identifier.doi10.1016/J.METABOL.2020.154400
dc.identifier.issn0026-0495
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/106210
dc.identifier.weblinkhttps://www.metabolismjournal.com/article/S0026-0495(20)30264-X/fulltext
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofMetabolism: Clinical and Experimental
dc.relation.pages154400 (1-16)
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enMyocardial injury
dc.subject.enDyslipidaemia
dc.subject.enAtherosclerotic mice
dc.subject.enMyocardial metabolic remodelling
dc.subject.enMitochondria
dc.titleEnhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern.
dc.typeJournalArticle
dspace.entity.typePublication