Journal Article

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

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

2016

Overview

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 H 2 O 2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H 2 O 2 . 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.

• Publisher: Springer Science and Business Media LLC,Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Animals / Cardiology / Coronary circulation; Coronary microcirculation; Diabetes; Mitochondria; Obesity; Animals; Coronary Vessels; DNA Damage; DNA Fragmentation; DNA, Mitochondrial; Disease Models, Animal; Metabolic Syndrome X; Mitochondria; Oxidative Stress; Rats; Rats, Zucker; Reactive Oxygen Species; Vasodilation; Physiology; Cardiology and Cardiovascular Medicine; Physiology (medical) / Coronary Vessels / Coronary Vessels - metabolism / Coronary Vessels - physiopathology / Disease Models, Animal / DNA Damage / DNA Damage - physiology / DNA Fragmentation / DNA, Mitochondrial / DNA, Mitochondrial - metabolism / Medicine / Medicine & Public Health / Metabolic Syndrome / Metabolic Syndrome - metabolism / Metabolic Syndrome - physiopathology / Mitochondria / Mitochondria - metabolism / Original Contribution / Oxidative Stress / Oxidative Stress - physiology / Rats / Rats, Zucker / Reactive Oxygen Species / Reactive Oxygen Species - metabolism / Vasodilation / Vasodilation - physiology