Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload.

TitleCardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload.
Publication TypeJournal Article
Year of Publication2015
AuthorsYancey, DM, Guichard, JL, Ahmed, MI, Zhou, L, Murphy, MP, Johnson, MS, Benavides, GA, Collawn, J, Darley-Usmar, V, Dell'Italia, LJ
JournalAm J Physiol Heart Circ Physiol
Date Published2015 Mar 15
KeywordsAnimals, Antioxidants, Cytoskeleton, Desmin, Disease Models, Animal, Heart Failure, Male, Membrane Potential, Mitochondrial, Mitochondria, Heart, Myocardial Contraction, Myocytes, Cardiac, Oxidative Stress, Rats, Sprague-Dawley, Reactive Oxygen Species, Time Factors, Tubulin, Ubiquinone, Ventricular Dysfunction, Left, Ventricular Function, Left

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.

Alternate JournalAm. J. Physiol. Heart Circ. Physiol.
Citation Key10.1152/ajpheart.00638.2014
PubMed ID25599572
PubMed Central IDPMC4360051
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
R00 HL095648 / HL / NHLBI NIH HHS / United States
R01 HL121206 / HL / NHLBI NIH HHS / United States
T32 HL072757 / HL / NHLBI NIH HHS / United States