title: Xanthine oxidase contributes to mitochondrial ROS generation in an experimental model of cocaine-induced diastolic dysfunction.
abstract: Recent studies have shown that long-term cocaine use induces diastolic impairment and a myocardial oxidative stress. Recently, we have reported that cocaine-induced cardiac dysfunction may be due to a mitochondrial reactive oxygen species (ROS) overproduction, which occurs at the same time as xanthine oxidase (XO) activation. In this work, we hypothesized that XO activation contributes to mitochondrial ROS overproduction, which in turn contributes to diastolic dysfunction. To test this, we used a well-established in vivo model of cocaine-induced diastolic dysfunction. In this experimental model treated with or without allopurinol, an inhibitor of XO, we measured mitochondrial ROS production and function. Mitochondrial alterations were characterized by an increase in oxygen consumption through complexes I and III, a reduction in ATP production, and an increased ROS production specifically in isolated interfibrillar mitochondria. Allopurinol treatment prevented the rise in mitochondrial ROS levels and the decrease in ATP production. In the same way, allopurinol treatment improved ventricular relaxation with a decrease in Tau, an index of left ventricle relaxation and of end-diastolic pressure volume relation. These results confirmed the critical role of XO in the sequence of events leading to cocaine-induced cardiac dysfunction.
authors.affiliation: University of Rouen, INSERM, Rouen, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Vergeade
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: Cathy
authors.initials: C
authors.lastname: Vendeville
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Christelle
authors.initials: C
authors.lastname: Monteil
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003042:Cocaine; D003971:Diastole; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013481:Superoxides; D000493:Allopurinol; D000255:Adenosine Triphosphate; D014969:Xanthine Oxidase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D003042:Cocaine