Downregulation of growth arrest‑specific transcript 5 alleviates palmitic acid‑induced myocardial inflammatory injury through the miR‑26a/HMGB1/NF‑κB axis

  • Authors:
    • Qingxiong Yue
    • Cuiting Zhao
    • Yonghuai Wang
    • Lanting Zhao
    • Qing Zhu
    • Guangyuan Li
    • Nan Wu
    • Dalin Jia
    • Chunyan Ma
  • View Affiliations

  • Published online on: October 25, 2018     https://doi.org/10.3892/mmr.2018.9593
  • Pages: 5742-5750
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Palmitic acid (PA) can induce lipotoxic damage to cardiomyocytes, although its precise mechanism of action has not been completely elucidated. Growth arrest‑specific transcript 5 (GAS5) is a long noncoding RNA that serves a regulatory role in several pathological processes, including tumorigenesis, stroke, cardiac fibrosis and osteoarthritis; however, its role in PA‑induced myocardial injury remains elusive. The present study aimed to explore the role and underlying mechanism of GAS5 on PA‑induced myocardial injury. The expression of GAS5 in PA‑treated cardiomyocytes (H9c2 cells) was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and its effects on PA‑induced myocardial injury were measured by Cell Counting Kit‑8 and lactate dehydrogenase (LDH) assays. The activities of cytokines and nuclear factor (NF)‑κB were also detected by enzyme‑linked immunosorbent assay, while interactions between GAS5 and microRNA (miR)‑26a were evaluated by luciferase reporter assay and RT‑qPCR. The regulation of GAS5 on high mobility group box 1 (HMGB1) expression was detected by RT‑qPCR and western blotting. The results demonstrated that GAS5 was significantly upregulated in cardiomyocytes following treatment with PA. GAS5‑knockdown increased the viability of PA‑treated cardiomyocytes and reduced the activity of LDH, tumor necrosis factor‑α and interleukin‑1β. Furthermore, the present study identified that GAS5 specifically binds to miR‑26a, and a reciprocal negative regulation exists between the two. The present study also demonstrated that GAS5 downregulation inhibited HMGB1 expression and NF‑κB activation, while these suppressive effects were mediated by miR‑26a. In conclusion, the present study demonstrated that PA can induce GAS5 expression and that the downregulation of GAS5 alleviated PA‑induced myocardial inflammatory injury through the miR‑26a/HMGB1/NF‑κB axis. These data may provide a novel insight into the mechanism of myocardial lipotoxic injury.

References

1 

NCD Risk Factor Collaboration (NCD-RisC): Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: A pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet. 390:2627–2642. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Boden G: Obesity and free fatty acids. Endocrinol Metab Clin North Am. 37(635–646): viii–ix. 2008.

3 

Djoussé L, Benkeser D, Arnold A, Kizer JR, Zieman SJ, Lemaitre RN, Tracy RP, Gottdiener JS, Mozaffarian D, Siscovick DS, et al: Plasma free fatty acids and risk of heart failure: The Cardiovascular Health Study. Circ Heart Fail. 6:964–969. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Zou L, Li X, Wu N, Jia P, Liu C and Jia D: Palmitate induces myocardial lipotoxic injury via the endoplasmic reticulum stress-mediated apoptosis pathway. Mol Med Rep. 16:6934–6939. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Wang Y, Qian Y, Fang Q, Zhong P, Li W, Wang L, Fu W, Zhang Y, Xu Z, Li X and Liang G: Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat Commun. 8:139972017. View Article : Google Scholar : PubMed/NCBI

6 

Zeng C, Zhong P, Zhao Y, Kanchana K, Zhang Y, Khan ZA, Chakrabarti S, Wu L, Wang J and Liang G: Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-κB both in vitro and in vivo. J Mol Cell Cardiol. 79:1–12. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Sun W, Yang Y, Xu C and Guo J: Regulatory mechanisms of long noncoding RNAs on gene expression in cancers. Cancer Genet. 216–217:105–110. 2017. View Article : Google Scholar

8 

Ratajczak MZ, Shin DM, Schneider G, Ratajczak J and Kucia M: Parental imprinting regulates insulin-like growth factor signaling: A Rosetta Stone for understanding the biology of pluripotent stem cells, aging and cancerogenesis. Leukemia. 27:773–779. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Lee JT: The X as model for RNA's niche in epigenomic regulation. Cold Spring Harb Perspect Biol. 2:a0037492010. View Article : Google Scholar : PubMed/NCBI

10 

Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P, et al: Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 43:621–629. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Sen R, Ghosal S, Das S, Balti S and Chakrabarti J: Competing endogenous RNA: The key to posttranscriptional regulation. ScientificWorldJournal. 2014:8962062014. View Article : Google Scholar : PubMed/NCBI

12 

Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, et al: MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 22:8031–8041. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Wang Y, Zhang Y, Yang T, Zhao W, Wang N, Li P, Zeng X and Zhang W: Long non-coding RNA MALAT1 for promoting metastasis and proliferation by acting as a ceRNA of miR-144-3p in osteosarcoma cells. Oncotarget. 8:59417–59434. 2017.PubMed/NCBI

14 

Coccia EM, Cicala C, Charlesworth A, Ciccarelli C, Rossi GB, Philipson L and Sorrentino V: Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol. 12:3514–3521. 1992. View Article : Google Scholar : PubMed/NCBI

15 

Zhang Z, Zhu Z, Watabe K, Zhang X, Bai C, Xu M, Wu F and Mo YY: Negative regulation of lncRNA GAS5 by miR-21. Cell Death Differ. 20:1558–1568. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Ma C, Shi X, Zhu Q, Li Q, Liu Y, Yao Y and Song Y: The growth arrest-specific transcript 5 (GAS5): A pivotal tumor suppressor long noncoding RNA in human cancers. Tumour Biol. 37:1437–1444. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Chen F, Zhang L, Wang E, Zhang C and Li X: LncRNA GAS5 regulates ischemic stroke as a competing endogenous RNA for miR-137 to regulate the Notch1 signaling pathway. Biochem Biophys Res Commun. 496:184–190. 2018. View Article : Google Scholar : PubMed/NCBI

18 

Yu F, Zheng J, Mao Y, Dong P, Lu Z, Li G, Guo C, Liu Z and Fan X: Long Non-coding RNA growth arrest-specific transcript 5 (GAS5) inhibits liver fibrogenesis through a mechanism of competing endogenous RNA. J Biol Chem. 290:28286–28298. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Tao H, Zhang JG, Qin RH, Dai C, Shi P, Yang JJ, Deng ZY and Shi KH: LncRNA GAS5 controls cardiac fibroblast activation and fibrosis by targeting miR-21 via PTEN/MMP-2 signaling pathway. Toxicology. 386:11–18. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Song J, Ahn C, Chun CH and Jin EJ: A long non-coding RNA, GAS5, plays a critical role in the regulation of miR-21 during osteoarthritis. J Orthop Res. 32:1628–1635. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Yan C, Chen J and Chen N: Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability. Sci Rep. 6:226402016. View Article : Google Scholar : PubMed/NCBI

22 

Brookheart RT, Michel CI, Listenberger LL, Ory DS and Schaffer JE: The non-coding RNA gadd7 is a regulator of lipid-induced oxidative and endoplasmic reticulum stress. J Biol Chem. 284:7446–7454. 2009. View Article : Google Scholar : PubMed/NCBI

23 

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

24 

Yao L, Lv X and Wang X: MicroRNA 26a inhibits HMGB1 expression and attenuates cardiac ischemia-reperfusion injury. J Pharmacol Sci. 131:6–12. 2016. View Article : Google Scholar : PubMed/NCBI

25 

He Q, Tan J, Yu B, Shi W and Liang K: Long noncoding RNA HIF1A-AS1A reduces apoptosis of vascular smooth muscle cells: Implications for the pathogenesis of thoracoabdominal aorta aneurysm. Pharmazie. 70:310–315. 2015.PubMed/NCBI

26 

Wang J, Chen L, Li H, Yang J, Gong Z, Wang B and Zhao X: Clopidogrel reduces apoptosis and promotes proliferation of human vascular endothelial cells induced by palmitic acid via suppression of the long non-coding RNA HIF1A-AS1 in vitro. Mol Cell Biochem. 404:203–210. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Kino T, Hurt DE, Ichijo T, Nader N and Chrousos GP: Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 3:ra82010. View Article : Google Scholar : PubMed/NCBI

28 

Keenan CR, Schuliga MJ and Stewart AG: Pro-inflammatory mediators increase levels of the noncoding RNA GAS5 in airway smooth muscle and epithelial cells. Can J Physiol Pharmacol. 93:203–206. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Rashid F, Shah A and Shan G: Long non-coding RNAs in the cytoplasm. Genomics Proteomics Bioinformatics. 14:73–80. 2016. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

December 2018
Volume 18 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yue, Q., Zhao, C., Wang, Y., Zhao, L., Zhu, Q., Li, G. ... Ma, C. (2018). Downregulation of growth arrest‑specific transcript 5 alleviates palmitic acid‑induced myocardial inflammatory injury through the miR‑26a/HMGB1/NF‑κB axis. Molecular Medicine Reports, 18, 5742-5750. https://doi.org/10.3892/mmr.2018.9593
MLA
Yue, Q., Zhao, C., Wang, Y., Zhao, L., Zhu, Q., Li, G., Wu, N., Jia, D., Ma, C."Downregulation of growth arrest‑specific transcript 5 alleviates palmitic acid‑induced myocardial inflammatory injury through the miR‑26a/HMGB1/NF‑κB axis". Molecular Medicine Reports 18.6 (2018): 5742-5750.
Chicago
Yue, Q., Zhao, C., Wang, Y., Zhao, L., Zhu, Q., Li, G., Wu, N., Jia, D., Ma, C."Downregulation of growth arrest‑specific transcript 5 alleviates palmitic acid‑induced myocardial inflammatory injury through the miR‑26a/HMGB1/NF‑κB axis". Molecular Medicine Reports 18, no. 6 (2018): 5742-5750. https://doi.org/10.3892/mmr.2018.9593