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

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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 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. 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 Ca2+ 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.

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Acknowledgments

This work was supported in part by the Natural Science Foundation of China 81400198 and 81270171, as well as the Innovation Team Grant of Shaanxi Province (No. 2014KCT-20).

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    Authors and Affiliations

    1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

      Jiaxing Wang, Nan Hu, Wenjun Yu, Na Li, Min Liu, Beilei Gao, Guoyong Zhang, Yingmei Zhang & Haichang Wang

    2. State Key Laboratory of Military Stomatology, School of Stomatology, Fourth Military Medical University, Xi’an, 710032, China

      Songhe Lu

    3. Department of Epidemiology, School of Public Health, Fourth Military Medical University, Xi’an, 710032, China

      Songhe Lu

    4. Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

      Qijun Zheng

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    1. Jiaxing Wang
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    Jiaxing Wang, Songhe Lu and Qijun Zheng have contributed equally to this work.

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    Wang, J., Lu, S., Zheng, Q. et al. Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction. Cardiovasc Toxicol 16, 235–243 (2016). https://doi.org/10.1007/s12012-015-9331-1

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