title: Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage.
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.
authors.affiliation: Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy.|Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Giacinta
authors.initials: G
authors.lastname: Guarini
authors.affiliation: Division of Cardiology, Tokai University Oiso Hospital, Oiso, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kiyooka
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Vahagn
authors.initials: V
authors.lastname: Ohanyan
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.|Department of Biomedical Science, University of Nottingham, Semenyih, Malaysia.
authors.forename: Yuh Fen
authors.initials: YF
authors.lastname: Pung
authors.affiliation: Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Marzilli
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Yeong Renn
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Chwen Lih
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Kang
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Hardwick
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Kolz
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, USA.
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.affiliation: Department of Biomedical Sciences, University of South Alabama, Mobile, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Shokolenko
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Dobson
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts, Boston, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Fenton
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA. wchilian@neomed.edu.
authors.forename: William M
authors.identifier: http://orcid.org/0000-0003-4522-7914
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology*; D004249:DNA Damage / Q000502:physiology; D053938:DNA Fragmentation; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004195:Disease Models, Animal; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species
keywords: Coronary circulation; Coronary microcirculation; Diabetes; Mitochondria; Obesity