Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage
- 510 Downloads
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.
KeywordsCoronary microcirculation Obesity Diabetes Coronary circulation Mitochondria
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).
Compliance with ethical standards
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.
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.
- 13.Holloway GP, Snook LA, Harris RJ, Glatz JF, Luiken JJ, Bonen A (2011) In obese Zucker rats, lipids accumulate in the heart despite normal mitochondrial content, morphology and long-chain fatty acid oxidation. J Physiol 589:169–180. doi: 10.1113/jphysiol.2010.198663 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and Standards Committee, European Association of Echocardiography (2005) Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18:1440–1463. doi: 10.1016/j.echo.2005.10.005 CrossRefPubMedGoogle Scholar
- 25.Mozaffari, Baban B, Liu JY, Abebe W, Sullivan JC, El-Marakby A (2011) Mitochondrial complex I and NAD(P)H oxidase are major sources of exacerbated oxidative stress in pressure-overloaded ischemic-reperfused hearts. Basic Res Cardiol 106:287–297. doi: 10.1007/s00395-011-0150-7 CrossRefPubMedGoogle Scholar
- 27.Ohanyan V, Yin L, Bardakjian R, Kolz C, Enrick M, Hakobyan T, Kmetz J, Bratz I, Luli J, Nagane M, Khan N, Hou H, Kuppusamy P, Graham J, Fu FK, Janota D, Oyewumi MO, Logan S, Lindner JR, Chilian WM (2015) Requisite role of Kv1.5 channels in coronary metabolic dilation. Circ Res 117:612–621. doi: 10.1161/CIRCRESAHA.115.306642 CrossRefPubMedGoogle Scholar
- 28.Pajuelo D, Fernandez-Iglesias A, Diaz S, Quesada H, Arola-Arnal A, Blade C, Salvado J, Arola L (2011) Improvement of mitochondrial function in muscle of genetically obese rats after chronic supplementation with proanthocyanidins. J Agric Food Chem 59:8491–8498. doi: 10.1021/jf201775v CrossRefPubMedGoogle Scholar
- 29.Pung YF, Rocic P, Murphy MP, Smith RA, Hafemeister J, Ohanyan V, Guarini G, Yin L, Chilian WM (2012) Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats. Arterioscler Thromb Vasc Biol 32:325–334. doi: 10.1161/ATVBAHA.111.241802 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Pung YF, Sam WJ, Stevanov K, Enrick M, Chen CL, Kolz C, Thakker P, Hardwick JP, Chen YR, Dyck JR, Yin L, Chilian WM (2013) Mitochondrial oxidative stress corrupts coronary collateral growth by activating adenosine monophosphate activated kinase-alpha signaling. Arterioscler Thromb Vasc Biol 33:1911–1919. doi: 10.1161/ATVBAHA.113.301591 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Yang XM, Cui L, White J, Kuck J, Ruchko MV, Wilson GL, Alexeyev M, Gillespie MN, Downey JM, Cohen MV (2015) Mitochondrially targeted Endonuclease III has a powerful anti-infarct effect in an in vivo rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 110:3. doi: 10.1007/s00395-014-0459-0 CrossRefPubMedPubMedCentralGoogle Scholar