title: Sarcoendoplasmic reticulum Ca(2+) ATPase. A critical target in chlorine inhalation-induced cardiotoxicity.
abstract: Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation-induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute high-concentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration-approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia-reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine- and istaroxime-treated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure.
authors.affiliation: 1 Pediatric Airway Research Center, Department of Pediatrics, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Shama
authors.initials: S
authors.lastname: Ahmad
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmad
authors.forename: Tara B
authors.initials: TB
authors.lastname: Hendry-Hofer
authors.forename: Joan E
authors.initials: JE
authors.lastname: Loader
authors.forename: William C
authors.initials: WC
authors.lastname: Claycomb
authors.forename: Olivier
authors.initials: O
authors.lastname: Mozziconacci
authors.forename: Christian
authors.initials: C
authors.lastname: Schöneich
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.forename: Roger L
authors.initials: RL
authors.lastname: Powell
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Chandler
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: Livia A
authors.initials: LA
authors.lastname: Veress
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D020013:Calcium Signaling; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002713:Chlorine / Q000633:toxicity*; D005043:Etiocholanolone / Q000031:analogs & derivatives / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology*; D019570:Inhalation Exposure; D008297:Male; D008929:Mitochondria, Heart; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D000069458:Ranolazine / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D013861:Thiocyanates / Q000494:pharmacology
chemical_list: D000975:Antioxidants; C506948:Atp2a2 protein, rat; D002316:Cardiotonic Agents; D013861:Thiocyanates; D002713:Chlorine; C024553:sodium thiocyanate; D000255:Adenosine Triphosphate; D005043:Etiocholanolone; D000069458:Ranolazine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C468128:Istaroxime
keywords: cardiac; chlorine; inhalation; ranolazine; sarcoendoplasmic reticulum Ca2+ATPase