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

  • Giacinta Guarini
  • Takahiko Kiyooka
  • Vahagn Ohanyan
  • Yuh Fen Pung
  • Mario Marzilli
  • Yeong Renn Chen
  • Chwen Lih Chen
  • Patrick T. Kang
  • James P. Hardwick
  • Christopher L. Kolz
  • Liya Yin
  • Glenn L. Wilson
  • Inna Shokolenko
  • James G. DobsonJr.
  • Richard Fenton
  • William M. Chilian
Original Contribution

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.

Keywords

Coronary microcirculation Obesity Diabetes Coronary circulation Mitochondria 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Giacinta Guarini
    • 1
    • 3
  • Takahiko Kiyooka
    • 2
  • Vahagn Ohanyan
    • 3
  • Yuh Fen Pung
    • 3
    • 4
  • Mario Marzilli
    • 1
  • Yeong Renn Chen
    • 3
  • Chwen Lih Chen
    • 3
  • Patrick T. Kang
    • 3
  • James P. Hardwick
    • 3
  • Christopher L. Kolz
    • 3
  • Liya Yin
    • 3
  • Glenn L. Wilson
    • 5
  • Inna Shokolenko
    • 6
  • James G. DobsonJr.
    • 7
  • Richard Fenton
    • 7
  • William M. Chilian
    • 3
  1. 1.Cardio-Thoracic and Vascular DepartmentUniversity of PisaPisaItaly
  2. 2.Division of CardiologyTokai University Oiso HospitalOisoJapan
  3. 3.Department of Integrative Medical SciencesNortheast Ohio Medical UniversityRootstownUSA
  4. 4.Department of Biomedical ScienceUniversity of NottinghamSemenyihMalaysia
  5. 5.Department of Cell Biology and NeuroscienceUniversity of South AlabamaMobileUSA
  6. 6.Department of Biomedical SciencesUniversity of South AlabamaMobileUSA
  7. 7.Department of Microbiology and Physiological SystemsUniversity of MassachusettsBostonUSA

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