Abstract
Tobacco smoking is a risk factor for many diseases, and nicotine is a major component of tobacco. Our previous work revealed that nicotine can induce myocardial fibrosis. This study aimed to investigate whether nicotine can induce cardiomyocyte apoptosis and to explore the mechanisms involved. Cardiomyocytes were exposed to different nicotine concentrations for 48 h. MTT assay showed that the viability of cardiomyocytes was significantly inhibited by nicotine in a dose- and time-dependent manner. Loss of mitochondrial membrane potential, nuclear and DNA defragmentation determined by TUNEL and ELISA assays, and morphological alterations all revealed the pro-apoptotic property of nicotine. Meanwhile, miR-133, a muscle-specific microRNA, was markedly downregulated by nicotine. Consistently, caspase-9, a target gene for miR-133, was significantly upregulated, leading to an increase in caspase-3, in nicotine-treated cardiomyocytes compared to non-treated cells. Furthermore, ERK1/2 protein levels were considerably downregulated, along with reduction of serum response factor (SRF), which is a downstream target protein of ERK1/2 and an upstream transactivator of miR-133 as well. Our findings therefore revealed that inhibition of the ERK1/2–SRF–miR-133 signaling pathway to increase caspases-9 and −3 is a novel mechanism for nicotine to induce cardiomyocyte apoptosis and these tobacco smokers.
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Acknowledgments
This work was supported in part by the National Basic Research Program of China (973 Program) (2013CB531104), the National Nature Science Foundation of China (nos. 81230081, 31171094, and 30901208), and the Postgraduate Innovation Fund of Heilongjiang province (YJSCX2012-245HLJ).
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Lu Wang and Xuelian Li contributed equally to this work.
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Wang, L., Li, X., Zhou, Y. et al. Downregulation of miR-133 via MAPK/ERK signaling pathway involved in nicotine-induced cardiomyocyte apoptosis. Naunyn-Schmiedeberg's Arch Pharmacol 387, 197–206 (2014). https://doi.org/10.1007/s00210-013-0929-1
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DOI: https://doi.org/10.1007/s00210-013-0929-1