Abstract
Viral myocarditis has been found to be one of the leading causes of sudden death in young adults. However, no effective drugs have been developed to intervene the progression of myocarditis. Accordingly, the present study is carried out to explore the protective role played by melatonin in the setting of viral myocarditis with a focus on Mst1-Hippo pathway, mitochondrial dysfunction and ER stress. Cardiac function was determined via echocardiographic examination. Mitochondrial function and ER stress were detected via ELISA, western blots, and immunofluorescence. Our data demonstrated that virus injection induced cardiac dysfunction as evidenced by reduced contractile function in myocardium. Besides, LDH release assay and western blotting analysis demonstrated that cardiomyocyte death was activated by virus injection. Interestingly, melatonin treatment improved cardiac function and repressed virus-mediated cardiomyocyte apoptosis. At the molecular levels, mitochondrial dysfunction was induced by virus infection, as indicated by mitochondrial membrane potential reduction, mPTP opening rate elevation and caspase-9-related apoptosis activation. Besides, ER stress parameters were also elevated in virus-treated cardiomyocytes. Interestingly, melatonin treatment maintained mitochondrial dysfunction and repressed ER stress. To the end, we found that Mst1 was upregulated by virus infection; this effect was attenuated through supplementation with melatonin. However, Mst1 overexpression reduced the beneficial impact exerted by melatonin on cardiomyocyte viability, mitochondrial function and ER homeostasis. Our study illustrated that melatonin treatment attenuated viral myocarditis via sustaining cardiomyocyte viability, repressing mitochondrial dysfunction and inhibiting ER stress in a manner dependent on Mst1 inhibition.
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Funding
This study is supported by the Natural Science Foundation of Guangdong Province of China (No: 2018A030313067), Key Specialist Department Training Project of Foshan City, Guangdong Province of China (No: Fspy 3-2015034), Science and Technology Innovation Project from Foshan, Guangdong (FS0AA-KJ218-1301-0006 and FS0AA-KJ218-1301-0010).
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HCOY, YT, and JKZ conceived the research; YT and YLZ performed the experiments; all authors participated in discussing and revising the manuscript.
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Ouyang, H., Zhong, J., Lu, J. et al. Inhibitory effect of melatonin on Mst1 ameliorates myocarditis through attenuating ER stress and mitochondrial dysfunction. J Mol Hist 50, 405–415 (2019). https://doi.org/10.1007/s10735-019-09836-w
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DOI: https://doi.org/10.1007/s10735-019-09836-w