Overexpression of mitochondrial creatine kinase preserves cardiac energetics without ameliorating murine chronic heart failure.

Autor: Cao F; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Maguire ML; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; Centre for Preclinical Imaging, Sherrington Building, Crown Street, Liverpool, UK., McAndrew DJ; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Lake HA; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Neubauer S; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Zervou S; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Schneider JE; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.; Experimental and Preclinical Imaging Centre (ePIC), Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK., Lygate CA; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. clygate@well.ox.ac.uk.; The BHF Centre for Research Excellence, Oxford and The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. clygate@well.ox.ac.uk.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2020 Jan 10; Vol. 115 (2), pp. 12. Date of Electronic Publication: 2020 Jan 10.
DOI: 10.1007/s00395-020-0777-3
Abstrakt: Mitochondrial creatine kinase (Mt-CK) is a major determinant of cardiac energetic status and is down-regulated in chronic heart failure, which may contribute to disease progression. We hypothesised that cardiomyocyte-specific overexpression of Mt-CK would mitigate against these changes and thereby preserve cardiac function. Male Mt-CK overexpressing mice (OE) and WT littermates were subjected to transverse aortic constriction (TAC) or sham surgery and assessed by echocardiography at 0, 3 and 6 weeks alongside a final LV haemodynamic assessment. Regardless of genotype, TAC mice developed progressive LV hypertrophy, dilatation and contractile dysfunction commensurate with pressure overload-induced chronic heart failure. There was a trend for improved survival in OE-TAC mice (90% vs 73%, P = 0.08), however, OE-TAC mice exhibited greater LV dilatation compared to WT and no functional parameters were significantly different under baseline conditions or during dobutamine stress test. CK activity was 37% higher in OE-sham versus WT-sham hearts and reduced in both TAC groups, but was maintained above normal values in the OE-TAC hearts. A separate cohort of mice received in vivo cardiac 31 P-MRS to measure high-energy phosphates. There was no difference in the ratio of phosphocreatine-to-ATP in the sham mice, however, PCr/ATP was reduced in WT-TAC but preserved in OE-TAC (1.04 ± 0.10 vs 2.04 ± 0.22; P = 0.007). In conclusion, overexpression of Mt-CK activity prevented the changes in cardiac energetics that are considered hallmarks of a failing heart. This had a positive effect on early survival but was not associated with improved LV remodelling or function during the development of chronic heart failure.
Databáze: MEDLINE
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