title: Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload.
abstract: Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β₂-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.
authors.affiliation: UAB Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Yancey
authors.affiliation: UAB Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Jason L
authors.initials: JL
authors.lastname: Guichard
authors.affiliation: UAB Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Mustafa I
authors.initials: MI
authors.lastname: Ahmed
authors.affiliation: UAB Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Lufang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, United Kingdom; and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; UAB Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; UAB Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Benavides
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: James
authors.initials: J
authors.lastname: Collawn
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; UAB Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
authors.affiliation: Department of Veterans Affairs Medical Center, Birmingham, Alabama; UAB Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama; louis.dellitalia@va.gov.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D000975:Antioxidants; D003893:Desmin; D017382:Reactive Oxygen Species; D014404:Tubulin; D014451:Ubiquinone
keywords: cardiomyocyte; heart failure; mitochondria