Abstract
Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac fibrosis and hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived reactive oxygen species (ROS) level and apoptosis, decreased activity of manganese superoxide dismutase (Mn-SOD); while silencing of lncDACH1 attenuated ROS production, mitochondrial dysfunction, cell apoptosis, and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose. LncDACH1 directly bound to sirtuin3 (SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition, SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bugger, H., Witt, C.N., and Bode, C. (2016). Mitochondrial sirtuins in the heart. Heart Fail Rev 21, 519–528.
Cai, B., Zhang, Y., Zhao, Y., Wang, J., Li, T., Zhang, Y., Jiang, Y., Jin, X., Xue, G., Li, P., et al. (2019). Long noncoding RNA-DACH1 (dachshund homolog 1) regulates cardiac function by inhibiting SERCA2a (sarcoplasmic reticulum calcium ATPase 2a). Hypertension 74, 833–842.
Cai, B., Ma, W., Ding, F., Zhang, L., Huang, Q., Wang, X., Hua, B., Xu, J., Li, J., Bi, C., et al. (2018). The long noncoding RNA carel controls cardiac regeneration. J Am Coll Cardiol 72, 534–550.
Cai, B., Ma, W., Wang, X., Sukhareva, N., Hua, B., Zhang, L., Xu, J., Li, X., Li, S., Liu, S., et al. (2020). Targeting lncdach1 promotes cardiac repair and regeneration after myocardium infarction. Cell Death Differ 27, 2158–2175.
Chen, H., and Shan, G. (2020). The physiological function of long-noncoding RNAs. Noncoding RNA Res 5, 178–184.
Dikalova, A.E., Itani, H.A., Nazarewicz, R.R., McMaster, W.G., Flynn, C. R., Uzhachenko, R., Fessel, J.P., Gamboa, J.L., Harrison, D.G., and Dikalov, S.I. (2017). Sirt3 impairment and SOD2 hyperacetylation in vascular oxidative stress and hypertension. Circ Res 121, 564–574.
Feng, Y., Xu, W., Zhang, W., Wang, W., Liu, T., and Zhou, X. (2019). LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy. Theranostics 9, 4558–4566.
Gao, J., Feng, Z., Wang, X., Zeng, M., Liu, J., Han, S., Xu, J., Chen, L., Cao, K., Long, J., et al. (2018). Sirt3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. Cell Death Differ 25, 229–240.
Huynh, K., Bernardo, B.C., McMullen, J.R., and Ritchie, R.H. (2014). Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 142, 375–415.
Jia, G., Hill, M.A., and Sowers, J.R. (2018). Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res 122, 624–638.
Koentges, C., Pfeil, K., Meyer-Steenbuck, M., Lother, A., Hoffmann, M. M., Odening, K.E., Hein, L., Bode, C., and Bugger, H. (2016). Preserved recovery of cardiac function following ischemia-reperfusion in mice lacking SIRT3. Can J Physiol Pharmacol 94, 72–80.
Li, X., Luo, S., Zhang, J., Yuan, Y., Jiang, W., Zhu, H., Ding, X., Zhan, L., Wu, H., Xie, Y., et al. (2019). LncRNA H19 alleviated myocardial I/RI via suppressing miR-877-3p/Bcl-2-mediated mitochondrial apoptosis. Mol Ther Nucleic Acids 17, 297–309.
Long, B., Yang, X., Xu, X., Li, X., Xu, X., Zhang, X., and Zhang, S. (2020). Long noncoding RNA ASB16-AS1 inhibits adrenocortical carcinoma cell growth by promoting ubiquitination of RNA-binding protein HuR. Cell Death Dis 11, 995.
Luo, S., Zhang, M., Wu, H., Ding, X., Li, D., Dong, X., Hu, X., Su, S., Shang, W., Wu, J., et al. (2021). Sail: A new conserved anti-fibrotic lncRNA in the heart. Basic Res Cardiol 116, 15.
Marwick, T.H., Ritchie, R., Shaw, J.E., and Kaye, D. (2018). Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J Am Coll Cardiol 71, 339–351.
Pi, H., Xu, S., Reiter, R.J., Guo, P., Zhang, L., Li, Y., Li, M., Cao, Z., Tian, L., Xie, J., et al. (2015). Sirt3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 11, 1037–1051.
Piccoli, M.T., Gupta, S.K., Viereck, J., Foinquinos, A., Samolovac, S., Kramer, F.L., Garg, A., Remke, J., Zimmer, K., Batkai, S., et al. (2017). Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction. Circ Res 121, 575–583.
Qu, X., Du, Y., Shu, Y., Gao, M., Sun, F., Luo, S., Yang, T., Zhan, L., Yuan, Y., Chu, W., et al. (2017). Miat is a pro-fibrotic long non-coding RNA governing cardiac fibrosis in post-infarct myocardium. Sci Rep 7, 42657.
Rashid, F., Shah, A., and Shan, G. (2016). Long non-coding RNAs in the cytoplasm. Genomics Proteomics BioInf 14, 73–80.
Song, S., Ding, Y., Dai, G., Zhang, Y., Xu, M., Shen, J., Chen, T., Chen, Y., and Meng, G. (2021). Sirtuin 3 deficiency exacerbates diabetic cardiomyopathy via necroptosis enhancement and NLRP3 activation. Acta Pharmacol Sin 42, 230–241.
Sultana, M.R., Bagul, P.K., Katare, P.B., Anwar Mohammed, S., Padiya, R., and Banerjee, S.K. (2016). Garlic activates Sirt-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes. Life Sci 164, 42–51.
Tao, R., Coleman, M.C., Pennington, J.D., Ozden, O., Park, S.H., Jiang, H., Kim, H.S., Flynn, C.R., Hill, S., Hayes McDonald, W., et al. (2010). Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 40, 893–904.
Wang, C., Liu, G., Yang, H., Guo, S., Wang, H., Dong, Z., Li, X., Bai, Y., and Cheng, Y. (2021). MALAT1-mediated recruitment of the histone methyltransferase EZH2 to the microRNA-22 promoter leads to cardiomyocyte apoptosis in diabetic cardiomyopathy. Sci Total Environ 766, 142191.
Wang, K., Liu, F., Zhou, L.Y., Long, B., Yuan, S.M., Wang, Y., Liu, C.Y., Sun, T., Zhang, X.J., and Li, P.F. (2014). The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res 114, 1377–1388.
Wang, Z.Q., He, C.Y., Hu, L., Shi, H.P., Li, J.F., Gu, Q.L., Su, L.P., Liu, B. Y., Li, C., and Zhu, Z. (2017). Long noncoding RNA UCA1 promotes tumour metastasis by inducing GRK2 degradation in gastric cancer. Cancer Lett 408, 10–21.
Xie, X., Wang, L., Zhao, B., Chen, Y., and Li, J. (2017). SIRT3 mediates decrease of oxidative damage and prevention of ageing in porcine fetal fibroblasts. Life Sci 177, 41–48.
Xu, W., Deng, B., Lin, P., Liu, C., Li, B., Huang, Q., Zhou, H., Yang, J., and Qu, L. (2020). Ribosome profiling analysis identified a KRAS-interacting microprotein that represses oncogenic signaling in hepatocellular carcinoma cells. Sci China Life Sci 63, 529–542.
Yang, F., Qin, Y., Wang, Y., Li, A., Lv, J., Sun, X., Che, H., Han, T., Meng, S., Bai, Y., et al. (2018). LncRNA KCNQ1OT1 mediates pyroptosis in diabetic cardiomyopathy. Cell Physiol Biochem 50, 1230–1244.
Yu, B., and Shan, G. (2016). Functions of long noncoding RNAs in the nucleus. Nucleus 7, 155–166.
Zhang, Y., Jiao, L., Sun, L., Li, Y., Gao, Y., Xu, C., Shao, Y., Li, M., Li, C., Lu, Y., et al. (2018). LncRNA ZFAS1 as a SERCA2a inhibitor to cause intracellular Ca2+ overload and contractile dysfunction in a mouse model of myocardial infarction. Circ Res 122, 1354–1368.
Zheng, J., Huang, X., Tan, W., Yu, D., Du, Z., Chang, J., Wei, L., Han, Y., Wang, C., Che, X., et al. (2016). Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat Genet 48, 747–757.
Zhou, Y., Chung, A.C.K., Fan, R., Lee, H.M., Xu, G., Tomlinson, B., Chan, J.C.N., and Kong, A.P.S. (2017). Sirt3 deficiency increased the vulnerability of pancreatic beta cells to oxidative stress-induced dysfunction. Antioxid Redox Signal 27, 962–976.
Zhuo, C., Jiang, R., Lin, X., and Shao, M. (2017). LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy. Oncotarget 8, 1429–1437.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81730012, 81872871, and 82070283) and CAMS Innovation Fund for Medical Sciences (2020-I2M-5-003).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Compliance and ethics
The author(s) declare that they have no conflict of interest.
Supplementary Materials
Rights and permissions
About this article
Cite this article
Zhang, Q., Li, D., Dong, X. et al. LncDACH1 promotes mitochondrial oxidative stress of cardiomyocytes by interacting with sirtuin3 and aggravates diabetic cardiomyopathy. Sci. China Life Sci. 65, 1198–1212 (2022). https://doi.org/10.1007/s11427-021-1982-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-021-1982-8