title: Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats.
abstract: Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca(2+)-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury.
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.
authors.forename: Nelson
authors.initials: N
authors.lastname: Escobales
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.
authors.forename: Rebeca E
authors.initials: RE
authors.lastname: Nuñez
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.
authors.forename: Sehwan
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Parodi-Rullan
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.
authors.forename: Sylvette
authors.initials: S
authors.lastname: Ayala-Peña
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sacher
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Skoda
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; Department of Physical Medicine and Rehabilitation, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Frontera
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico. Electronic address: sabzali.javadov@upr.edu.
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000188:drug therapy*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D011916:Rats, Inbred F344; D020127:Recovery of Function
chemical_list: D002316:Cardiotonic Agents; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C523959:XJB-5-131; D006861:Hydrogen Peroxide
keywords: Aging; Heart; Ischemia/reperfusion; Mitochondria; ROS scavenger; XJB-5-131