Downregulation of microRNA‑1 attenuates glucose‑induced apoptosis by regulating the liver X receptor α in cardiomyocytes

Cheng,Yongxia; Zhao,Wei; Zhang,Xiaodong; Sun,Lixin; Yang,Heran; Wang,Ying; Cao,Yong; Chu,Yanhui; Liu,Guibo

doi:10.3892/etm.2018.6388

Downregulation of microRNA‑1 attenuates glucose‑induced apoptosis by regulating the liver X receptor α in cardiomyocytes

Authors:
- Yongxia Cheng
- Wei Zhao
- Xiaodong Zhang
- Lixin Sun
- Heran Yang
- Ying Wang
- Yong Cao
- Yanhui Chu
- Guibo Liu
View Affiliations

Affiliations: Department of Pathology, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, P.R. China, Department of Anatomy, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, P.R. China, Department of Infectious Disease, Hongqi Hospital, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, P.R. China, School of Adult Education, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, P.R. China, Department of Laboratory Medicine, Hongqi Hospital, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, P.R. China, Medical Pharmacology Research Center, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, P.R. China
Published online on: July 2, 2018 https://doi.org/10.3892/etm.2018.6388
Pages: 1814-1824
Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diabetic cardiomyopathy (DCM) is characterized by abnormal myocardial structure or performance. It has been suggested that microRNA‑1 (miR‑1) may be abnormally expressed in the hearts of patients with diabetes. In the present study, the role of miR‑1 in glucose‑induced apoptosis and its underlying mechanism of action was investigated in rat cardiomyocyte H9C2 cells. Cells were transfected with anti‑miR‑1 or miR‑1‑overexpression plasmids and the expression of miR‑1 and liver X receptor α (LXRα) were determined by reverse transcription‑quantitative polymerase chain reaction analysis. The proportion of apoptotic cells was determined using an Annexin‑V‑FITC apoptosis detection kit and the mitochondrial membrane potential (ΔΨ) was measured following staining with rhodamine 123. In addition, the expression of apoptosis‑associated proteins was measured by western blot analysis. The results demonstrated that expression of miR‑1 was significantly increased, whereas the expression of LXRα was significantly decreased in H9C2 cells following treatment with glucose. miR‑1 knockdown significantly inhibited apoptosis, increased the ΔΨ and suppressed the cleavage of poly (adenosine diphosphate‑ribose) polymerase, caspase‑3 and caspase‑9. It also significantly downregulated the expression of Bcl‑2 and upregulated the expression of Bax. In addition, it was demonstrated that miR‑1 regulates LXRα; transfection with anti‑miR‑1 significantly increased the expression of LXRα. Furthermore, treatment of cells with the LXR agonist GW3965 inhibited apoptosis in glucose‑induced anti‑miR‑1 cells. These results suggest a novel function of miR‑1: The regulation of cardiomyocyte apoptosis via LXRα, and provide novel insights into regarding the complex mechanisms involved in DCM.

View Figures

View References

1	Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, et al: Heart disease and stroke statistics-2017 update: A report from the american heart association. Circulation. 135:e146–e603. 2017. View Article : Google Scholar : PubMed/NCBI
2	Mishra PK, Ying W, Nandi SS, Bandyopadhyay GK, Patel KK and Mahata SK: Diabetic cardiomyopathy: An immunometabolic perspective. Front Endocrinol (Lausanne). 8:722017. View Article : Google Scholar : PubMed/NCBI
3	Gersh BJ, Sliwa K, Mayosi BM and Yusuf S: Novel therapeutic concepts: The epidemic of cardiovascular disease in the developing world: Global implications. Eur Heart J. 31:642–648. 2010. View Article : Google Scholar : PubMed/NCBI
4	Aneja A, Tang WH, Bansilal S, Garcia MJ and Farkouh ME: Diabetic cardiomyopathy: Insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med. 121:748–757. 2008. View Article : Google Scholar : PubMed/NCBI
5	Shivalkar B, Dhondt D, Goovaerts I, Van Gaal L, Bartunek J, Van Crombrugge P and Vrints C: Flow mediated dilatation and cardiac function in type 1 diabetes mellitus. Am J Cardiol. 97:77–82. 2006. View Article : Google Scholar : PubMed/NCBI
6	Carugo S, Giannattasio C, Calchera I, Paleari F, Gorgoglione MG, Grappiolo A, Gamba P, Rovaris G, Failla M and Mancia G: Progression of functional and structural cardiac alterations in young normotensive uncomplicated patients with type 1 diabetes mellitus. J Hypertens. 19:1675–1680. 2001. View Article : Google Scholar : PubMed/NCBI
7	Pappachan JM, Varughese GI, Sriraman R and Arunagirinathan G: Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management. World J Diabetes. 4:177–189. 2013. View Article : Google Scholar : PubMed/NCBI
8	Karp X and Ambros V: Developmental biology. Encountering microRNAs in cell fate signaling. Science. 310:1288–1289. 2005. View Article : Google Scholar : PubMed/NCBI
9	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
10	Allegra A, Alonci A, Campo S, Penna G, Petrungaro A, Gerace D and Musolino C: Circulating microRNAs: New biomarkers in diagnosis, prognosis and treatment of cancer (review). Int J Oncol. 41:1897–1912. 2012. View Article : Google Scholar : PubMed/NCBI
11	Sayed D and Abdellatif M: MicroRNAs in development and disease. Physiol Rev. 91:827–887. 2011. View Article : Google Scholar : PubMed/NCBI
12	Shan ZX, Lin QX, Deng CY, Zhu JN, Mai LP, Liu JL, Fu YH, Liu XY, Li YX, Zhang YY, et al: miR-1/miR-206 regulate Hsp60 expression contributing to glucose-mediated apoptosis in cardiomyocytes. FEBS Lett. 584:3592–3600. 2010. View Article : Google Scholar : PubMed/NCBI
13	Lu H, Buchan RJ and Cook SA: Microrna-223 regulates glut4 expression and cardiomyocyte glucose metabolism. Cardiovasc Res. 86:410–420. 2010. View Article : Google Scholar : PubMed/NCBI
14	Horie T, Ono K, Nishi H, Iwanaga Y, Nagao K, Kinoshita M, Kuwabara Y, Takanabe R, Hasegawa K, Kita T and Kimura T: MicroRNA-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiac myocytes. Biochem Biophys Res Commun. 389:315–320. 2009. View Article : Google Scholar : PubMed/NCBI
15	Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, et al: The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 13:486–491. 2007. View Article : Google Scholar : PubMed/NCBI
16	Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL and Wang DZ: The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 38:228–233. 2006. View Article : Google Scholar : PubMed/NCBI
17	Zhong D, Huang G, Zhang Y, Zeng Y, Xu Z, Zhao Y, He X and He F: MicroRNA-1 and microRNA-206 suppress LXRalpha-induced lipogenesis in hepatocytes. Cell Signal. 25:1429–1437. 2013. View Article : Google Scholar : PubMed/NCBI
18	Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ, Zhang Y, Stayrook KR, Suen C, Otto KA, et al: Antidiabetic action of a liver × receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem. 278:1131–1136. 2003. View Article : Google Scholar : PubMed/NCBI
19	Liu Y, Yan C, Wang Y, Nakagawa Y, Nerio N, Anghel A, Lutfy K and Friedman TC: Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice. Endocrinology. 147:5061–5068. 2006. View Article : Google Scholar : PubMed/NCBI
20	Cannon MV, Silljé HHW, Sijbesma JWA, Khan MAF, Steffensen KR, van Gilst WH and de Boer RA: LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes. Diabetologia. 59:634–643. 2016. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Qi D and Young LH: AMPK: Energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol Metab. 26:422–429. 2015. View Article : Google Scholar : PubMed/NCBI
23	Kumarapeli AR and Wang X: Genetic modification of the heart: Chaperones and the cytoskeleton. J Mol Cell Cardiol. 37:1097–1109. 2004.PubMed/NCBI
24	Renault TT, Teijido O, Antonsson B, Dejean LM and Manon S: Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-x(L): Keep your friends close but your enemies closer. Int J Biochem Cell Biol. 45:64–67. 2013. View Article : Google Scholar : PubMed/NCBI
25	He Q, Pu J, Yuan A, Yao T, Ying X, Zhao Y, Xu L, Tong H and He B: Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc Diabetol. 13:1492014. View Article : Google Scholar : PubMed/NCBI
26	Tarquini R, Lazzeri C, Pala L, Rotella CM and Gensini GF: The diabetic cardiomyopathy. Acta Diabetol. 48:173–181. 2011. View Article : Google Scholar : PubMed/NCBI
27	Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW and Grishman A: New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 30:595–602. 1972. View Article : Google Scholar : PubMed/NCBI
28	Ai J, Zhang R, Li Y, Pu J, Lu Y, Jiao J, Li K, Yu B, Li Z, Wang R, et al: Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem Biophys Res Commun. 391:73–77. 2010. View Article : Google Scholar : PubMed/NCBI
29	Fichtlscherer S, Zeiher AM and Dimmeler S: Circulating microRNAs: Biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol. 31:2383–2390. 2011. View Article : Google Scholar : PubMed/NCBI
30	Townley-Tilson WHD, Callis TE and Wang D: MicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease. Int J Biochem Cell Biol. 42:1252–1255. 2010. View Article : Google Scholar : PubMed/NCBI
31	Feng B, Cao Y, Chen S, Ruiz M and Chakrabarti S: Reprint of: miRNA-1 regulates endothelin-1 in diabetes. Life Sci. 118:275–280. 2014. View Article : Google Scholar : PubMed/NCBI
32	Yu XY, Song YH, Geng YJ, Lin QX, Shan ZX, Lin SG and Li Y: Glucose induces apoptosis of cardiomyocytes via microRNA-1 and IGF-1. Biochem Biophys Res Commun. 376:548–552. 2008. View Article : Google Scholar : PubMed/NCBI
33	Yu L, Yu H, Li X, Jin C, Zhao Y, Xu S and Sheng X: P38 MAPK/miR-1 are involved in the protective effect of EGCG in high glucose-induced C×43 downregulation in neonatal rat cardiomyocytes. Cell Biol Int. 40:934–942. 2016. View Article : Google Scholar : PubMed/NCBI
34	Zhai C, Tang G, Peng L, Hu H, Qian G, Wang S, Yao J and Zhang X, Fang Y, Yang S and Zhang X: Inhibition of microRNA-1 attenuates hypoxia/re-oxygenation-induced apoptosis of cardiomyocytes by directly targeting Bcl-2 but not GADD45Beta. Am J Transl Res. 7:1952–1962. 2015.PubMed/NCBI
35	Adams JM: Ways of dying: Multiple pathways to apoptosis. Genes Dev. 17:2481–2495. 2003. View Article : Google Scholar : PubMed/NCBI
36	Adams JM and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar : PubMed/NCBI
37	Pawlowski J and Kraft AS: Bax-induced apoptotic cell death. Proc Natl Acad Sci USA. 97:529–531. 2000. View Article : Google Scholar : PubMed/NCBI
38	Pena-Blanco A and Garcia-Saez AJ: Bax, bak and beyond-mitochondrial performance in apoptosis. FEBS J. 285:416–431. 2018. View Article : Google Scholar : PubMed/NCBI
39	Brown LM, Hanna DT, Khaw SL and Ekert PG: Dysregulation of BCL-2 family proteins by leukemia fusion genes. J Biol Chem. 292:14325–14333. 2017. View Article : Google Scholar : PubMed/NCBI
40	Ma Z, Deng C, Hu W, Zhou J, Fan C, Di S, Liu D, Yang Y and Wang D: Liver × receptors and their agonists: Targeting for cholesterol homeostasis and cardiovascular diseases. Curr Issues Mol Biol. 22:41–64. 2017. View Article : Google Scholar : PubMed/NCBI
41	Fessler MB: The challenges and promise of targeting the liver × receptors for treatment of inflammatory disease. Pharmacol Ther. 181:1–12. 2018. View Article : Google Scholar : PubMed/NCBI
42	Parikh M, Patel K, Soni S and Gandhi T: Liver X receptor: A cardinal target for atherosclerosis and beyond. J Atheroscler Thromb. 21:519–531. 2014.PubMed/NCBI
43	Ceroi A, Masson D, Roggy A, Roumier C, Chague C, Gauthier T, Philippe L, Lamarthee B, Angelot-Delettre F, Bonnefoy F, et al: LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis. Blood. 128:2694–2707. 2016. View Article : Google Scholar : PubMed/NCBI
44	Cao G, Bales KR, DeMattos RB and Paul SM: Liver X receptor-mediated gene regulation and cholesterol homeostasis in brain: Relevance to Alzheimer's disease therapeutics. Curr Alzheimer Res. 4:179–184. 2007. View Article : Google Scholar : PubMed/NCBI
45	Traversari C, Sozzani S, Steffensen KR and Russo V: LXR-dependent and -independent effects of oxysterols on immunity and tumor growth. Eur J Immunol. 44:1896–1903. 2014. View Article : Google Scholar : PubMed/NCBI
46	Calkin AC and Tontonoz P: Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 13:213–224. 2012. View Article : Google Scholar : PubMed/NCBI
47	Im SS and Osborne TF: Liver × receptors in atherosclerosis and inflammation. Circ Res. 108:996–1001. 2011. View Article : Google Scholar : PubMed/NCBI
48	Lee HJ, Ryu JM, Jung YH, Lee SJ, Kim JY, Lee SH, Hwang IK, Seong JK and Han HJ: High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells. Sci Rep. 6:367462016. View Article : Google Scholar : PubMed/NCBI
49	Ou Z, Wada T, Gramignoli R, Li S, Strom SC, Huang M and Xie W: MicroRNA hsa-miR-613 targets the human LXRalpha gene and mediates a feedback loop of LXRalpha autoregulation. Mol Endocrinol. 25:584–596. 2011. View Article : Google Scholar : PubMed/NCBI
50	Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ and Tontonoz P: LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA. 98:507–512. 2001. View Article : Google Scholar : PubMed/NCBI
51	Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ and Edwards PA: Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem. 275:14700–14707. 2000. View Article : Google Scholar : PubMed/NCBI
52	Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM and Mangelsdorf DJ: Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 289:1524–1529. 2000. View Article : Google Scholar : PubMed/NCBI
53	Laffitte BA, Joseph SB, Chen M, Castrillo A, Repa J, Wilpitz D, Mangelsdorf D and Tontonoz P: The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Mol Cell Biol. 23:2182–2191. 2003. View Article : Google Scholar : PubMed/NCBI
54	Jiang XC, Beyer TP, Li Z, Liu J, Quan W, Schmidt RJ, Zhang Y, Bensch WR, Eacho PI and Cao G: Enlargement of high density lipoprotein in mice via liver × receptor activation requires apolipoprotein e and is abolished by cholesteryl ester transfer protein expression. J Biol Chem. 278:49072–49078. 2003. View Article : Google Scholar : PubMed/NCBI
55	Mak PA, Kast-Woelbern HR, Anisfeld AM and Edwards PA: Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res. 43:2037–2041. 2002. View Article : Google Scholar : PubMed/NCBI
56	Javitt NB: Cholesterol, hydroxycholesterols, and bile acids. Biochem Biophys Res Commun. 292:1147–1153. 2002. View Article : Google Scholar : PubMed/NCBI
57	Niesor EJ, Flach J, Lopes-Antoni I, Perez A and Bentzen CL: The nuclear receptors FXR and LXRalpha: Potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases. Curr Pharm Des. 7:231–259. 2001. View Article : Google Scholar : PubMed/NCBI
58	Jianhua L, Xueqin M and Jifen H: Expression and clinical significance of LXRα and SREBP-1c in placentas of preeclampsia. Open Med (Wars). 11:292–296. 2016.PubMed/NCBI
59	Harasiuk D, Baranowski M, Zabielski P, Chabowski A and Górski J: Liver × receptor agonist to901317 prevents diacylglycerols accumulation in the heart of streptozotocin-diabetic rats. Cell Physiol Biochem. 39:350–359. 2016. View Article : Google Scholar : PubMed/NCBI
60	Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, et al: Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci USA. 100:5419–5424. 2003. View Article : Google Scholar : PubMed/NCBI