title: Role of oxidative stress in ischemia-reperfusion-induced alterations in myofibrillar ATPase activities and gene expression in the heart.
abstract: Ischemia-reperfusion (IR) in the heart has been shown to produce myofibrillar remodeling and depress Ca2+ sensitivity of myofilaments; however, the mechanisms for these alterations are not clearly understood. In view of the role of oxidative stress in cardiac dysfunction due to IR, isolated rat hearts were subjected to global ischemia for 30 min followed by a 30-minute period of reperfusion. IR was found to induce cardiac dysfunction, as reflected by depressed LVDP, +dP/dt, and -dP/dt, and elevated LVEDP, and to reduce myofibrillar Ca2+-stimulated ATPase activity. These changes were simulated by perfusing the hearts with a mixture of xanthine plus xanthine oxidase, which is known to generate oxyradicals. The alterations in cardiac function and myofibrillar Ca2+-stimulated ATPase in IR hearts were attenuated by pretreatment with antioxidants (superoxide dismutase plus catalase, and N-acetylcysteine) and leupeptin, an inhibitor of Ca2+-dependent protease. The levels of mRNA for myosin heavy chain isoforms (alpha-MHC and beta-MHC) and myosin light chain (MLC1) were depressed in IR hearts. These changes in gene expression due to IR were prevented upon perfusing the hearts with superoxide plus catalase, with N-acetylcysteine, or with leupeptin. The results suggest that oxidative stress due to IR injury and associated proteolysis play an important role in inducing changes in myofibrillar Ca2+-stimulated ATPase activity and gene expression in the heart.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, Faculty of Medicine, University of Manitoba, 351 Tache Avenue, Winnipeg, MB R2H2A6, Canada.
authors.forename: Srilekha
authors.initials: S
authors.lastname: Maddika
authors.forename: Vijayan
authors.initials: V
authors.lastname: Elimban
authors.forename: Donald
authors.initials: D
authors.lastname: Chapman
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D009210:Myofibrils / Q000187:drug effects / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D017725:Ventricular Pressure; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D007976:Leupeptins; C000594638:MYH7 protein, rat; D018994:Myosin Light Chains; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C076659:myosin light chain I; D019820:Xanthine; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; C032854:leupeptin; D000111:Acetylcysteine