Cardiac-Specific Knockout of ET A Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

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 (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 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. 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 Ca 2+ 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.