title: Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction.
abstract: Paraquat (1,1'-dim ethyl-4-4'-bipyridinium dichloride), a highly toxic quaternary ammonium herbicide widely used in agriculture, exerts potent toxic prooxidant effects resulting in multi-organ failure including the lung and heart although the underlying mechanism remains elusive. Recent evidence suggests possible involvement of endothelin system in paraquat-induced acute lung injury. This study was designed to examine the role of endothelin receptor A (ETA) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ETA receptor knockout mice were challenged to paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, as well as apoptosis and mitochondrial damage. Levels of the mitochondrial proteins for biogenesis and oxidative phosphorylation including UCP2, HSP90 and PGC1α were evaluated. Our results revealed that paraquat elicited cardiac enlargement, mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic and end-diastolic diameters as well as reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, overt apoptosis and mitochondrial damage. ETA receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ETA receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ETA receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Military Stomatology, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, China.|Department of Epidemiology, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Songhe
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Guoyong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. zhangym197951@126.com.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. wanghc@fmmu.edu.cn.
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D066126:Cardiotoxicity; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010269:Paraquat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000172:deficiency* / Q000235:genetics; D000071246:Uncoupling Protein 2 / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D018841:HSP90 Heat-Shock Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D044022:Receptor, Endothelin A; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D010269:Paraquat
keywords: Apoptosis; Cardiac function; Endothelin; Mitochondria; Paraquat