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Necrostatin-1 Protects Against Paraquat-Induced Cardiac Contractile Dysfunction via RIP1-RIP3-MLKL-Dependent Necroptosis Pathway

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Abstract

Paraquat is a highly toxic prooxidant that triggers oxidative stress and multi-organ failure including that of the heart. To date, effective treatment of paraquat toxicity is still not established. Necroptosis, a newly discovered form of programmed cell death, was recently shown to be strongly associated with cardiovascular disease. Receptor interaction proteins 1 (RIP1), receptor interaction proteins 3 (RIP3), and mixed lineage kinase domain like (MLKL) are key proteins in the necroptosis pathway. Necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis which acts by blocking the interaction between RIP1 and RIP3. In the present study, we studied the effect of Nec-1 on paraquat-induced cardiac contractile dysfunction and reactive oxygen species (ROS) production in the heart tissues using a mouse model. Our results revealed impaired contractile function, deranged intracellular Ca2+ handling and echocardiographic abnormalities in mice challenged with paraquat. We further found enhanced expressions of RIP1, RIP3, and MLKL along with overproduction of ROS in mice heart tissues. Nec-1 pre-treatment prevented cardiac contractile dysfunction in paraquat-challenged mice. Furthermore, Nec-1 reduced RIP1–RIP3 interaction, down-regulated the RIP1–RIP3–MLKL signal pathway, and dramatically inhibited the production of ROS. Collectively, these findings suggest that Nec-1 alleviated paraquat-induced myocardial contractile dysfunction through inhibition of necroptosis, an effect which was likely mediated via the RIP1–RIP3–MLKL signaling cascade. Further, ROS appeared to play an important role in this process. Thus, this process may represent a novel therapeutic strategy for the treatment of paraquat-induced cardiac contractile dysfunction.

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    Authors and Affiliations

    1. Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

      Liping Zhang & Qiming Feng

    2. Shanghai Pudong Newarea Healthcare Hospital for Women and Children, Shanghai, 201200, China

      Teng Wang

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    1. Liping Zhang
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    2. Qiming Feng
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    3. Teng Wang
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    Contributions

    LPZ, QMF, and TW performed parts of the experiments; LPZ and TW wrote article and carried out data analysis; LPZ, QMF carried out the study design, supervised and reviewed manuscript. All authors read and approved the final manuscript.

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    Correspondence to Liping Zhang.

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    The authors declare that they have no competing interests.

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    Liping Zhang and Qiming Feng are contributed equally to this work.

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    Zhang, L., Feng, Q. & Wang, T. Necrostatin-1 Protects Against Paraquat-Induced Cardiac Contractile Dysfunction via RIP1-RIP3-MLKL-Dependent Necroptosis Pathway. Cardiovasc Toxicol 18, 346–355 (2018). https://doi.org/10.1007/s12012-017-9441-z

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