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Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage

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Abstract

Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.

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Acknowledgments

The authors wish to acknowledge the following grant support: HL032788, HL083366, HL115114, Fibus Family Foundation (WMC); R15HL115540, HL103227, DK095895, AHA14BGIA18770028 (LY); AHA POST4360030 (VO); HL083237 (Y-RC); AHA POST2290021 (YFP) and ES03456 (GLW).

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    Authors and Affiliations

    1. Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy

      Giacinta Guarini & Mario Marzilli

    2. Division of Cardiology, Tokai University Oiso Hospital, Oiso, Japan

      Takahiko Kiyooka

    3. Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA

      Giacinta Guarini, Vahagn Ohanyan, Yuh Fen Pung, Yeong Renn Chen, Chwen Lih Chen, Patrick T. Kang, James P. Hardwick, Christopher L. Kolz, Liya Yin & William M. Chilian

    4. Department of Biomedical Science, University of Nottingham, Semenyih, Malaysia

      Yuh Fen Pung

    5. Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, USA

      Glenn L. Wilson

    6. Department of Biomedical Sciences, University of South Alabama, Mobile, USA

      Inna Shokolenko

    7. Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA

      James G. Dobson Jr. & Richard Fenton

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    1. Giacinta Guarini
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    Correspondence to William M. Chilian.

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    Conflict of interest

    Dr. Wilson has an interest in the company Exscien, which is manufacturing and licensing the recombinant proteins. All other authors have nothing to disclose.

    Ethical standards

    All animal studies were performed using protocols approved by the Northeast Ohio Medical University Institutional Animal Care and Use Committee and comply with the ethical standards laid down in the 1964 Declaration of Helsinki and all later amendments. This manuscript does not contain clinical studies or patient data.

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    G. Guarini and T. Kiyooka contributed to a similar extent and should be considered joint first authors

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    Guarini, G., Kiyooka, T., Ohanyan, V. et al. Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage. Basic Res Cardiol 111, 29 (2016). https://doi.org/10.1007/s00395-016-0547-4

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