Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

详细信息    查看全文

• 作者：Jiaxing Wang ; Songhe Lu ; Qijun Zheng ; Nan Hu ; Wenjun Yu ; Na Li…
• 刊名：Cardiovascular Toxicology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：16
• 期：3
• 页码：235-243
• 全文大小：749 KB
• 刊物主题：Pharmacology/Toxicology; Cardiology;
• 出版者：Springer US
• ISSN：1559-0259
• 卷排序：16

文摘

Paraquat (1,1’-dimethyl-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 (ET_A) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ET_A 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 Ca2+ 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 Ca2+ handling, overt apoptosis and mitochondrial damage. ET_A receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ET_A receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca2+ defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ET_A receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.KeywordsParaquatEndothelinMitochondriaApoptosisCardiac function