Abstract
AIM: Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF).
METHODS: We assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)-lean (control) and ZSF1-obese rats, a metabolic risk-related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo.
RESULTS: At rest, mitochondrial Ca2+ concentration in ZSF1-obese was larger than in ZSF1-lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady-state levels were larger in ZSF1-obese. The half-widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half-times of the cytosolic Ca2+ transients were higher in ZSF1-obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1-obese.
CONCLUSION: The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.
Original language | English |
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Article number | e13378 |
Pages (from-to) | e13378 |
Journal | Acta Physiologica |
Volume | 228 |
Issue number | 3 |
Early online date | 13 Sept 2019 |
DOIs | |
Publication status | Published - Mar 2020 |
Bibliographical note
© 2019 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.Funding
We thank M. Goebel, Drs E. van Deel and M. Helmes (VUmc, Amsterdam, the Netherlands) for technical assistance and advice and Dr JL Martin (UIC, Chicago, USA) for construction of the MitoCam adenovirus. This study was supported by a Dutch Heart Foundation CVON (Cardiovasculair Onderzoek Nederland) grant (ARENA: Approaching Heart Failure By Translational Research Of RNA Mechanisms); a European Commission FP7‐Health‐2010 grant (MEDIA: MEtabolic Road to DIAstolic Heart Failure; 261409); the Portuguese Foundation for Science and Technology (grant UID/IC/00051/2013); Fundo Europeu de Desenvolvimento Regional (FEDER) through COMPETE 2020—Programa Operacional Competitividade e Internacionalização (POCI) (grant PTDC/DTP‐PIC/4104/2014) and the project DOCnet (NORTE‐01‐0145‐FEDER‐000003), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Daniela Miranda‐Silva was supported by Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/87556/2012). Glória Conceição was supported by Universidade do Porto/FMUP and by FSE—Fundo Social Europeu through NORTE2020—Programa Operacional Regional do Norte (NORTE‐08‐5369‐FSE‐000024—Programas Doutorais). We thank M. Goebel, Drs E. van Deel and M. Helmes (VUmc, Amsterdam, the Netherlands) for technical assistance and advice and Dr JL Martin (UIC, Chicago, USA) for construction of the MitoCam adenovirus. This study was supported by a Dutch Heart Foundation CVON (Cardiovasculair Onderzoek Nederland) grant (ARENA: Approaching Heart Failure By Translational Research Of RNA Mechanisms); a European Commission FP7-Health-2010 grant (MEDIA: MEtabolic Road to DIAstolic Heart Failure; 261409); the Portuguese Foundation for Science and Technology (grant UID/IC/00051/2013); Fundo Europeu de Desenvolvimento Regional (FEDER) through COMPETE 2020?Programa Operacional Competitividade e Internacionaliza??o (POCI) (grant PTDC/DTP-PIC/4104/2014) and the project DOCnet (NORTE-01-0145-FEDER-000003), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Daniela Miranda-Silva was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) (SFRH/BD/87556/2012). Gl?ria Concei??o was supported by Universidade do Porto/FMUP and by FSE?Fundo Social Europeu through NORTE2020?Programa Operacional Regional do Norte (NORTE-08-5369-FSE-000024?Programas Doutorais).
Funders | Funder number |
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Cardiovasculair Onderzoek Nederland | |
Ci?ncia e Tecnologia | |
Dutch Heart Foundation CVON | |
European Commission FP7-Health-2010 | |
European Commission FP7‐Health‐2010 | |
FMUP | |
FSE?Fundo Social Europeu | |
Norte Portugal Regional Operational Programme | |
Universidade do Porto/FMUP | |
Seventh Framework Programme | 261409 |
Faculty of Science and Engineering, University of Manchester | |
Fundação para a Ciência e a Tecnologia | SFRH/BD/87556/2012, UID/IC/00051/2013 |
European Social Fund | |
Universidade Do Porto | |
European Regional Development Fund | PTDC/DTP‐PIC/4104/2014, NORTE‐01‐0145‐FEDER‐000003 |
Stichting Diabetes Onderzoek Nederland |