Overexpression of miR-130a-3p attenuates cardiomyocyte hypertrophy_Journal of Biomedical Engineering

Authors：

WANG Xiaojiao ¹ , QU Jing ¹ , LI Dongxu ² , LI Junli ^1,3 , WU Wenchao ¹ ,  LIU Xiaojing ^1,3

1. Lab of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;
2. Department of Cardiac Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;
3. Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

LIU Xiaojing, Email: liuxq@scu.edu.cn

Keywords：

miR-130a-3p; myocardial hypertrophy; cardiomyocyte hypertrophy; pressure-overload; Akt

DOI：

10.7507/1001-5515.201911049

Video：

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This study aimed to explore the role of miR-130a-3p in cardiomyocyte hypertrophy and its underlying mechanisms. Pressure-overload induced myocardial hypertrophy mice model was constructed by thoracic aortic constriction (TAC). In vitro, norepinephrine (NE) was used to stimulate neonatal rat cardiomyocytes (NRCMs) and H9c2 rat cardiomyocytes to induce hypertrophic phenotypes. The expression of miR-130a-3p was detected in mice hypertrophic myocardium, hypertrophic NRCMs and H9c2 cells. The mimics and inhibitors of miR-130a-3p were transfected into H9c2 cells to observe the role of miR-130a-3p on the hypertrophic phenotype change of cardiomyocytes separately. Furthermore, whether miR-130a-3p regulated hypertrophic related signaling pathways was explored. The results showed that the expression of miR-130a-3p was significantly decreased in hypertrophic myocardium, hypertrophic NRCMs and H9c2 cells. After transfection of miR-130a-3p mimics, the expression of hypertrophic marker genes, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), and the cell surface area were notably down-regulated compared with the control group (mimics N.C. + NE group). But after transfection of miR-130a-3p inhibitor, the expression of ANP, BNP and β-MHC in H9c2 cells increased significantly, and the cell area increased further. By Western blot, it was found that the protein phosphorylation level of Akt and mTOR were down-regulated after over-expression of miR-130a-3p. These results suggest that miR-130a-3p mimics may alleviate the degree of cardiomyocyte hypertrophy, meanwhile its inhibitor can further aggravate cardiomyocyte hypertrophy. Over-expression of miR-130a-3p may attenuate cardiomyocytes hypertrophy by affecting the Akt pathway.

Citation： WANG Xiaojiao, QU Jing, LI Dongxu, LI Junli, WU Wenchao, LIU Xiaojing. Overexpression of miR-130a-3p attenuates cardiomyocyte hypertrophy. Journal of Biomedical Engineering, 2020, 37(2): 340-348. doi: 10.7507/1001-5515.201911049 Copy

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2.	Camacho Londoño J E, Tian Qinghai, Hammer K, et al. A background Ca²⁺ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling. Eur Heart J, 2015, 36(33): 2257-2266.
3.	Kehat I, Molkentin J D. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation, 2010, 122(25): 2727-2735.
4.	Magadum A, Ding Yishu, He Lan, et al. Live cell screening platform identifies PPARδ as a regulator of cardiomyocyte proliferation and cardiac repair. Cell Res, 2017, 27(8): 1002-1019.
5.	Omidkhoda N, Wallace Hayes A, Reiter R J, et al. The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy. Pharmacol Res, 2019, 150: 104516.
6.	Greco C M, Condorelli G. Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol, 2015, 12(8): 488-497.
7.	Zhou Tao, Qin G, Yang Liehong, et al. LncRNA XIST regulates myocardial infarction by targeting miR-130a-3p. J Cell Physiol, 2019, 234(6): 8659-8667.
8.	De Gonzalo-Calvo D, Cenario A, Garlaschelli K A, et al. Translating the microRNA signature of microvesicles derived from human coronary artery smooth muscle cells in patients with familial hypercholesterolemia and coronary artery disease. J Mol Cell Cardiol, 2017, 106: 55-67.
9.	Chen Li, Zhao Mingyue, Li Junli, et al. Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1. Cell Cycle, 2017, 16(4): 348-359.
10.	Wu Jiahan, Dong Tao, Chen Ting, et al. Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte. Metabolism, 2019, 103: 154006.
11.	Yang Xubin, Li Xiaoshan, Lin Qiongyan, et al. Up-regulation of microRNA-203 inhibits myocardial fibrosis and oxidative stress in mice with diabetic cardiomyopathy through the inhibition of PI3K/Akt signaling pathway via PIK3CA. Gene, 2019, 715: 143995.
12.	Sadiq S, Crowley T M, Charchar F J, et al. MicroRNAs in a hypertrophic heart: from foetal life to adulthood. Biol Rev Camb Philos Soc, 2017, 92(3): 1314-1331.
13.	Moghaddam A S, Afshari J T, Esmaeili S A, et al. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis, 2019, 285: 1-9.
14.	Zaglia T, Ceriotti P, Campo A, et al. Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy. Proc Natl Acad Sci U S A, 2017, 114(43): E9006-E9015.
15.	Yuan Weiwei, Tang Chunmei, Zhu Wensi, et al. CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy. Mol Cell Biochem, 2016, 412(1/2): 289-296.
16.	Elia L, Contu R, Quintavalle M, et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation, 2009, 120(23): 2377-2385.
17.	Nie Xiang, Fan Jiahui, Li Huaping, et al. miR-217 promotes cardiac hypertrophy and dysfunction by targeting PTEN. Mol Ther Nucleic Acids, 2018, 12: 254-266.
18.	Thienpont B, Aronsen J M, Robinson E L, et al. The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. J Clin Invest, 2017, 127(1): 335-348.
19.	Bao Qinxue, Zhao Mingyue, Chen Li, et al. MicroRNA-297 promotes cardiomyocyte hypertrophy via targeting sigma-1 receptor. Life Sci, 2017, 175: 1-10.
20.	Marques F Z, Vizi D, Khammy O, et al. The transcardiac gradient of cardio-microRNAs in the failing heart. Eur J Heart Fail, 2016, 18(8): 1000-1008.
21.	杨四宝, 高永建, 杨萍. 转化生长因子 β 与 microRNAs 的串话效应在心肌纤维化中的研究进展. 中国循环杂志, 2013, 28(7): 552-554.
22.	Travers J G, Kamal F A, Robbins J, et al. Cardiac fibrosis: the fibroblast awakens. Circ Res, 2016, 118(6): 1021-1040.
23.	朱永翔, 张耀庭, 王彤, 等. MicroRNA 在心肌纤维化中的研究进展. 心血管病学进展, 2018, 39(6): 903-906.
24.	Wang Chengyu, Li Xiangdan, Hao Zhihong, et al. Insulin-like growth factor-1 improves diabetic cardiomyopathy through antioxidative and anti-inflammatory processes along with modulation of Akt/GSK-3β signaling in rats. Korean J Physiol Pharmacol, 2016, 20(6): 613-619.
25.	Yang Fan, Li Ping, Li Haiyu, et al. microRNA-29b mediates the antifibrotic effect of tanshinone IIA in postinfarct cardiac remodeling. J Cardiovasc Pharmacol, 2015, 65(5): 456-464.
26.	陈兴, 成传访, 方燕龄, 等. mTOR 信号通路在心肌肥大中的作用. 中国医药导报, 2018, 15(7): 16-19.
27.	de Lima-Seolin B G, Nemec-Bakk A, Forsyth H, et al. Bucindolol modulates cardiac remodeling by attenuating oxidative stress in H9c2 cardiac cells exposed to norepinephrine. Oxid Med Cell Longev, 2019, 2019: 6325424.
28.	Yang Xiaomei, Chen Gang, Chen Zhengxu. MicroRNA-200a-3p is a positive regulator in cardiac hypertrophy through directly targeting WDR1 as well as modulating PTEN/PI3K/AKT/CREB/WDR1 signaling. J Cardiovasc Pharmacol, 2019, 74: 453-461.

1. Schiattarella G G, Hill J A. Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload. Circulation, 2015, 131(16): 1435-1447.
2. Camacho Londoño J E, Tian Qinghai, Hammer K, et al. A background Ca²⁺ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling. Eur Heart J, 2015, 36(33): 2257-2266.
3. Kehat I, Molkentin J D. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation, 2010, 122(25): 2727-2735.
4. Magadum A, Ding Yishu, He Lan, et al. Live cell screening platform identifies PPARδ as a regulator of cardiomyocyte proliferation and cardiac repair. Cell Res, 2017, 27(8): 1002-1019.
5. Omidkhoda N, Wallace Hayes A, Reiter R J, et al. The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy. Pharmacol Res, 2019, 150: 104516.
6. Greco C M, Condorelli G. Epigenetic modifications and noncoding RNAs in cardiac hypertrophy and failure. Nat Rev Cardiol, 2015, 12(8): 488-497.
7. Zhou Tao, Qin G, Yang Liehong, et al. LncRNA XIST regulates myocardial infarction by targeting miR-130a-3p. J Cell Physiol, 2019, 234(6): 8659-8667.
8. De Gonzalo-Calvo D, Cenario A, Garlaschelli K A, et al. Translating the microRNA signature of microvesicles derived from human coronary artery smooth muscle cells in patients with familial hypercholesterolemia and coronary artery disease. J Mol Cell Cardiol, 2017, 106: 55-67.
9. Chen Li, Zhao Mingyue, Li Junli, et al. Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1. Cell Cycle, 2017, 16(4): 348-359.
10. Wu Jiahan, Dong Tao, Chen Ting, et al. Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte. Metabolism, 2019, 103: 154006.
11. Yang Xubin, Li Xiaoshan, Lin Qiongyan, et al. Up-regulation of microRNA-203 inhibits myocardial fibrosis and oxidative stress in mice with diabetic cardiomyopathy through the inhibition of PI3K/Akt signaling pathway via PIK3CA. Gene, 2019, 715: 143995.
12. Sadiq S, Crowley T M, Charchar F J, et al. MicroRNAs in a hypertrophic heart: from foetal life to adulthood. Biol Rev Camb Philos Soc, 2017, 92(3): 1314-1331.
13. Moghaddam A S, Afshari J T, Esmaeili S A, et al. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis, 2019, 285: 1-9.
14. Zaglia T, Ceriotti P, Campo A, et al. Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy. Proc Natl Acad Sci U S A, 2017, 114(43): E9006-E9015.
15. Yuan Weiwei, Tang Chunmei, Zhu Wensi, et al. CDK6 mediates the effect of attenuation of miR-1 on provoking cardiomyocyte hypertrophy. Mol Cell Biochem, 2016, 412(1/2): 289-296.
16. Elia L, Contu R, Quintavalle M, et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation, 2009, 120(23): 2377-2385.
17. Nie Xiang, Fan Jiahui, Li Huaping, et al. miR-217 promotes cardiac hypertrophy and dysfunction by targeting PTEN. Mol Ther Nucleic Acids, 2018, 12: 254-266.
18. Thienpont B, Aronsen J M, Robinson E L, et al. The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. J Clin Invest, 2017, 127(1): 335-348.
19. Bao Qinxue, Zhao Mingyue, Chen Li, et al. MicroRNA-297 promotes cardiomyocyte hypertrophy via targeting sigma-1 receptor. Life Sci, 2017, 175: 1-10.
20. Marques F Z, Vizi D, Khammy O, et al. The transcardiac gradient of cardio-microRNAs in the failing heart. Eur J Heart Fail, 2016, 18(8): 1000-1008.
21. 杨四宝, 高永建, 杨萍. 转化生长因子 β 与 microRNAs 的串话效应在心肌纤维化中的研究进展. 中国循环杂志, 2013, 28(7): 552-554.
22. Travers J G, Kamal F A, Robbins J, et al. Cardiac fibrosis: the fibroblast awakens. Circ Res, 2016, 118(6): 1021-1040.
23. 朱永翔, 张耀庭, 王彤, 等. MicroRNA 在心肌纤维化中的研究进展. 心血管病学进展, 2018, 39(6): 903-906.
24. Wang Chengyu, Li Xiangdan, Hao Zhihong, et al. Insulin-like growth factor-1 improves diabetic cardiomyopathy through antioxidative and anti-inflammatory processes along with modulation of Akt/GSK-3β signaling in rats. Korean J Physiol Pharmacol, 2016, 20(6): 613-619.
25. Yang Fan, Li Ping, Li Haiyu, et al. microRNA-29b mediates the antifibrotic effect of tanshinone IIA in postinfarct cardiac remodeling. J Cardiovasc Pharmacol, 2015, 65(5): 456-464.
26. 陈兴, 成传访, 方燕龄, 等. mTOR 信号通路在心肌肥大中的作用. 中国医药导报, 2018, 15(7): 16-19.
27. de Lima-Seolin B G, Nemec-Bakk A, Forsyth H, et al. Bucindolol modulates cardiac remodeling by attenuating oxidative stress in H9c2 cardiac cells exposed to norepinephrine. Oxid Med Cell Longev, 2019, 2019: 6325424.
28. Yang Xiaomei, Chen Gang, Chen Zhengxu. MicroRNA-200a-3p is a positive regulator in cardiac hypertrophy through directly targeting WDR1 as well as modulating PTEN/PI3K/AKT/CREB/WDR1 signaling. J Cardiovasc Pharmacol, 2019, 74: 453-461.

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