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Questions {❓}

• Vogt AM, Kubler W (1998) Heart failure: is there an energy deficit contributing to contractile dysfunction?

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         headline:Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage
         description: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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      headline:Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage
      description: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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         Obesity
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         Cardiology
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            type:Organization
      name:James P. Hardwick
      affiliation:
            name:Northeast Ohio Medical University
            address:
               name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
               type:PostalAddress
            type:Organization
      name:Christopher L. Kolz
      affiliation:
            name:Northeast Ohio Medical University
            address:
               name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
               type:PostalAddress
            type:Organization
      name:Liya Yin
      affiliation:
            name:Northeast Ohio Medical University
            address:
               name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
               type:PostalAddress
            type:Organization
      name:Glenn L. Wilson
      affiliation:
            name:University of South Alabama
            address:
               name:Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, USA
               type:PostalAddress
            type:Organization
      name:Inna Shokolenko
      affiliation:
            name:University of South Alabama
            address:
               name:Department of Biomedical Sciences, University of South Alabama, Mobile, USA
               type:PostalAddress
            type:Organization
      name:James G. Dobson
      affiliation:
            name:University of Massachusetts
            address:
               name:Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA
               type:PostalAddress
            type:Organization
      name:Richard Fenton
      affiliation:
            name:University of Massachusetts
            address:
               name:Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA
               type:PostalAddress
            type:Organization
      name:William M. Chilian
      url:http://orcid.org/0000-0003-4522-7914
      affiliation:
            name:Northeast Ohio Medical University
            address:
               name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Division of Cardiology, Tokai University Oiso Hospital, Oiso, Japan
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Biomedical Science, University of Nottingham, Semenyih, Malaysia
      name:Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
      name:Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, USA
      name:Department of Biomedical Sciences, University of South Alabama, Mobile, USA
      name:Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA
      name:Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA
      name:Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, USA
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