Abstract
Pathological cardiac hypertrophy is the leading cause of heart failure, and miRNAs have been recognized as key factors in cardiac hypertrophy. This study aimed to elucidate whether miR-17-5p affects cardiac hypertrophy by targeting the mitochondrial fusion protein mitofusin 2 (Mfn2)-mediated phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and regulating autophagy. miR-17-5p expression was shown to be upregulated both in vivo and in vitro. In addition, a miR-17-5p inhibitor significantly reversed AngII-induced cell hypertrophy in neonatal rat left ventricle myocytes (NRVMs). In contrast to miR-17-5p expression, Mfn2 expression was inhibited in rat hearts at 4 weeks after transverse aortic constriction (TAC) and in an Ang II-induced cell hypertrophy model. We examined miR-17-5p targeting of Mfn2 by dual luciferase reporter and Western blot assays. In addition, we also verified the relationship between Mfn2 and the PI3K/AKT/mTOR pathway. Mfn2 overexpression attenuated miR-17-5p-induced cell hypertrophy, and in rat myocardial tissue, miR-17-5p induced autophagy inhibition. In summary, the results of the present study demonstrated that miR-17-5p inhibits Mfn2 expression, activates the PI3K/AKT/mTOR pathway and suppresses autophagy to promote cardiac hypertrophy.
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References
Shimizu, I., & Minamino, T. (2016). Physiological and pathological cardiac hypertrophy. Journal of Molecular and Cellular Cardiology, 97, 245–262. https://doi.org/10.1016/j.yjmcc.2016.06.001
Zhao, L., Wu, D., Sang, M., Xu, Y., Liu, Z., & Wu, Q. (2017). Stachydrine ameliorates isoproterenol-induced cardiac hypertrophy and fibrosis by suppressing inflammation and oxidative stress through inhibiting NF-κB and JAK/STAT signaling pathways in rats. International Immunopharmacology, 48, 102–109. https://doi.org/10.1016/j.intimp.2017.05.002
Xie, Y. P., Lai, S., Lin, Q. Y., Xie, X., Liao, J. W., Wang, H. X., et al. (2018). CDC20 regulates cardiac hypertrophy via targeting LC3-dependent autophagy. Theranostics, 8(21), 5995–6007. https://doi.org/10.7150/thno.27706
Sciarretta, S., Forte, M., Frati, G., & Sadoshima, J. (2018). New insights into the role of mTOR signaling in the cardiovascular system. Circulation Research, 122(3), 489–505. https://doi.org/10.1161/circresaha.117.311147
Oka, T., Akazawa, H., Naito, A. T., & Komuro, I. (2014). Angiogenesis and cardiac hypertrophy: Maintenance of cardiac function and causative roles in heart failure. Circulation Research, 114(3), 565–571. https://doi.org/10.1161/CIRCRESAHA.114.300507
Liesa, M., & Shirihai, O. S. (2013). Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metabolism, 17(4), 491–506. https://doi.org/10.1016/j.cmet.2013.03.002
de Brito, O. M., & Scorrano, L. (2008). Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature, 456(7222), 605–610. https://doi.org/10.1038/nature07534
Zhao, T., Huang, X., Han, L., Wang, X., Cheng, H., Zhao, Y., et al. (2012). Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. Journal of Biological Chemistry, 287(28), 23615–23625. https://doi.org/10.1074/jbc.M112.379164
Fang, X., Chen, X., Zhong, G., Chen, Q., & Hu, C. (2016). Mitofusin 2 downregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PI3K/Akt and mitochondrial apoptosis pathways. Journal of Cardiovascular Pharmacology, 67(2), 164–174. https://doi.org/10.1097/fjc.0000000000000333
Aoyagi, T., & Matsui, T. (2011). Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure. Current Pharmaceutical Design, 17(18), 1818–1824. https://doi.org/10.2174/138161211796390976
Hall, A. R., Burke, N., Dongworth, R. K., Kalkhoran, S. B., Dyson, A., Vicencio, J. M., et al. (2016). Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell Death and Disease, 7, e2238. https://doi.org/10.1038/cddis.2016.139
Yu, H., Guo, Y., Mi, L., Wang, X., Li, L., & Gao, W. (2011). Mitofusin 2 inhibits angiotensin II-induced myocardial hypertrophy. Journal of Cardiovascular Pharmacology and Therapeutics, 16(2), 205–211. https://doi.org/10.1177/1074248410385683
Bartel, D. P. (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136(2), 215–233. https://doi.org/10.1016/j.cell.2009.01.002
Wang, J., Liew, O. W., Richards, A. M., & Chen, Y. T. (2016). Overview of microRNAs in cardiac hypertrophy, fibrosis, and apoptosis. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms17050749
Shi, J. Y., Chen, C., Xu, X., & Lu, Q. (2019). miR-29a promotes pathological cardiac hypertrophy by targeting the PTEN/AKT/mTOR signalling pathway and suppressing autophagy. Acta Physiology (Oxford), 227(2), e13323. https://doi.org/10.1111/apha.13323
Du, W., Pan, Z., Chen, X., Wang, L., Zhang, Y., Li, S., et al. (2014). By targeting Stat3 microRNA-17-5p promotes cardiomyocyte apoptosis in response to ischemia followed by reperfusion. Cellular Physiology and Biochemistry, 34(3), 955–965. https://doi.org/10.1159/000366312
Liu, X., Xiao, J., Zhu, H., Wei, X., Platt, C., Damilano, F., et al. (2015). miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metabalism, 21(4), 584–595. https://doi.org/10.1016/j.cmet.2015.02.014
Huo, J. Y., Jiang, W. Y., Geng, J., Chen, C., Zhu, L., Chen, R., et al. (2019). Renal denervation attenuates pressure overload-induced cardiac remodelling in rats with biphasic regulation of autophagy. Acta Physiology (Oxford), 226(4), e13272. https://doi.org/10.1111/apha.13272
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., et al. (2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 8(4), 445–544. https://doi.org/10.4161/auto.19496
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12(1), 1–222. https://doi.org/10.1080/15548627.2015.1100356
Xue, R., Zhu, X., Jia, L., Wu, J., Yang, J., Zhu, Y., et al. (2019). Mitofusin2, a rising star in acute-on-chronic liver failure, triggers macroautophagy via the mTOR signalling pathway. Journal of Cellular and Molecular Medicine, 23(11), 7810–7818. https://doi.org/10.1111/jcmm.14658
Xue, R., Meng, Q., Lu, D., Liu, X., Wang, Y., & Hao, J. (2018). Mitofusin2 induces cell autophagy of pancreatic cancer through inhibiting the PI3K/Akt/mTOR signaling pathway. Oxidative Medicine and Cellular Longevity, 2018, 2798070. https://doi.org/10.1155/2018/2798070
Stefely, J. A., Zhang, Y., Freiberger, E. C., Kwiecien, N. W., Thomas, H. E., Davis, A. M., et al. (2020). Mass spectrometry proteomics reveals a function for mammalian CALCOCO1 in MTOR-regulated selective autophagy. Autophagy. https://doi.org/10.1080/15548627.2020.1719746
Mellis, D., & Caporali, A. (2018). MicroRNA-based therapeutics in cardiovascular disease: Screening and delivery to the target. Biochemical Society Transactions, 46(1), 11–21. https://doi.org/10.1042/BST20170037
Sivakumar, A., Subbiah, R., Balakrishnan, R., & Rajendhran, J. (2017). Cardiac mitochondrial dynamics: MiR-mediated regulation during cardiac injury. Journal of Molecular and Cellular Cardiology, 110, 26–34. https://doi.org/10.1016/j.yjmcc.2017.07.003
Samidurai, A., Roh, S. K., Prakash, M., Durrant, D., Salloum, F. N., Kukreja, R. C., et al. (2019). STAT3-miR-17/20 signaling axis plays a critical role in attenuating myocardial infarction following rapamycin treatment in diabetic mice. Cardiovascular Research. https://doi.org/10.1093/cvr/cvz315
Du, W. W., Li, X., Li, T., Li, H., Khorshidi, A., Liu, F., et al. (2015). The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4. Journal of Cell Sciences, 128(2), 293–304. https://doi.org/10.1242/jcs.158360
Mendell, J. T. (2008). miRiad Roles for the miR-17-92 cluster in development and disease. Cell, 133(2), 217–222. https://doi.org/10.1016/j.cell.2008.04.001
Li, S. H., Guo, J., Wu, J., Sun, Z., Han, M., Shan, S. W., et al. (2013). miR-17 targets tissue inhibitor of metalloproteinase 1 and 2 to modulate cardiac matrix remodeling. FASEB Journal, 27(10), 4254–4265. https://doi.org/10.1096/fj.13-231688
Xue, S., Liu, D., Zhu, W., Su, Z., Zhang, L., Zhou, C., et al. (2019). Circulating MiR-17-5p, MiR-126-5p and MiR-145-3p are novel biomarkers for diagnosis of acute myocardial infarction. Frontiers in Physiology, 10, 123. https://doi.org/10.3389/fphys.2019.00123
Fang, L., Ellims, A. H., Moore, X. L., White, D. A., Taylor, A. J., Chin-Dusting, J., et al. (2015). Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. Journal of Translational Medicine, 13, 314. https://doi.org/10.1186/s12967-015-0672-0
Qin, W., Zhang, Y. B. H., Deng, B. L., Liu, J., Zhang, H. L., & Jin, Z. L. (2019). MiR-17-5p modulates mitochondrial function of the genioglossus muscle satellite cells through targeting Mfn2 in hypoxia. Journal of Biological Regulators and Homeostatic Agents, 33(3), 753–761.
Shen, T., Zheng, M., Cao, C., Chen, C., Tang, J., Zhang, W., et al. (2007). Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis. Journal of Biological Chemistry, 282(32), 23354–23361. https://doi.org/10.1074/jbc.M702657200
Guan, X., Wang, L., Liu, Z., Guo, X., Jiang, Y., Lu, Y., et al. (2016). miR-106a promotes cardiac hypertrophy by targeting mitofusin 2. Journal of Molecular and Cellular Cardiology, 99, 207–217. https://doi.org/10.1016/j.yjmcc.2016.08.016
Song, M., Franco, A., Fleischer, J. A., Zhang, L., & Dorn, G. W., 2nd. (2017). Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metabolism, 26(6), 872-883.e875. https://doi.org/10.1016/j.cmet.2017.09.023
Xiong, W., Ma, Z., An, D., Liu, Z., Cai, W., Bai, Y., et al. (2019). Mitofusin 2 participates in mitophagy and mitochondrial fusion against angiotensin II-induced cardiomyocyte injury. Frontiers in Physiology, 10, 411. https://doi.org/10.3389/fphys.2019.00411
Delbridge, L. M. D., Mellor, K. M., Taylor, D. J., & Gottlieb, R. A. (2017). Myocardial stress and autophagy: Mechanisms and potential therapies. Nature Reviews Cardiology, 14(7), 412–425. https://doi.org/10.1038/nrcardio.2017.35
Li, Z., Wang, J., & Yang, X. (2015). Functions of autophagy in pathological cardiac hypertrophy. International Journal of Biological Sciences, 11(6), 672–678. https://doi.org/10.7150/ijbs.11883
Acknowledgements
This work was supported by The Six Talent Peaks Project in Jiangsu Province, China (No. 2016-WSN-103) and the Nantong Science and Technology Bureau, China (No. JC2018082; MS22018005).
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Xu, X., Su, Yl., Shi, Jy. et al. MicroRNA-17-5p Promotes Cardiac Hypertrophy by Targeting Mfn2 to Inhibit Autophagy. Cardiovasc Toxicol 21, 759–771 (2021). https://doi.org/10.1007/s12012-021-09667-w
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DOI: https://doi.org/10.1007/s12012-021-09667-w