title: High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation.
abstract: Hyperoxia exposure in mice leads to cardiac hypertrophy and voltage-gated potassium (Kv) channel remodeling. Because redox balance of pyridine nucleotides affects Kv function and hyperoxia alters cellular redox potential, we hypothesized that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias. In the present study, we investigated the electrical changes and redox abnormalities caused by 72h hyperoxia treatment in mice. Cardiac repolarization changes were assessed by acquiring electrocardiogram (ECG) and cardiac action potentials (AP). Biochemical assays were employed to identify the pyridine nucleotide changes, Kv1.5 expression and myocardial injury. Hyperoxia treatment caused marked bradycardia, arrhythmia and significantly prolonged (ms) the, RR (186.2 ± 10.7 vs. 146.4 ± 6.2), PR (46.8 ± 3.1 vs. 39.3 ± 1.6), QRS (10.8 ± 0.6 vs. 8.5 ± 0.2), QTc (57.1 ± 3.5 vs. 40 ± 1.4) and JT (13.4 ± 2.1 vs. 7.0 ± 0.5) intervals, when compared with normoxia group. Hyperoxia treatment also induced significant increase in cardiac action potential duration (APD) (ex-APD90; 73.8 ± 9.5 vs. 50.9 ± 3.1 ms) and elevated levels of serum markers of myocardial injury; cardiac troponin I (TnI) and lactate dehydrogenase (LDH). Hyperoxia exposure altered cardiac levels of mRNA/protein expression of; Kv1.5, Kvβ subunits and SiRT1, and increased ratios of reduced pyridine nucleotides (NADH/NAD & NADPH/NADP). Inhibition of SiRT1 in H9C2 cells using Splitomicin resulted in decreased SiRT1 and Kv1.5 expression, suggesting that SiRT1 may mediate Kv1.5 downregulation. In conclusion, the cardiotoxic effects of hyperoxia exposure involve ion channel disturbances and redox changes resulting in arrhythmias.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Chapalamadugu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Siva K
authors.initials: SK
authors.lastname: Panguluri
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Bennett
authors.affiliation: Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Narasaiah
authors.initials: N
authors.lastname: Kolliputi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA. Electronic address: stippara@health.usf.edu.
authors.forename: Srinivas M
authors.initials: SM
authors.lastname: Tipparaju
mesh_terms: D000200:Action Potentials; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001919:Bradycardia / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D004562:Electrocardiography; D006329:Heart Conduction System / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D018496:Hyperoxia / Q000097:blood / Q000150:complications*; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D019210:Troponin I / Q000097:blood
chemical_list: D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; C496982:Kcna5 protein, mouse; C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D019210:Troponin I; D009243:NAD; D009249:NADP; D007770:L-Lactate Dehydrogenase; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: ECG; Heart; Hyperoxia; Kvβ; Potassium channel; Redox