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MiR-132 Inhibits Expression of SIRT1 and Induces Pro-inflammatory Processes of Vascular Endothelial Inflammation through Blockade of the SREBP-1c Metabolic Pathway

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Abstract

Purpose

Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with pro-inflammatory processes and inflammatory changes in the endothelium, related to lipid metabolism. MicroRNA (miRNA) inhibition of inflammation related to SIRT1 has been shown to be a promising therapeutic approach for AS. However, the mechanism of action is unknown.

Methods

We investigated whether miRNAs regulate the SIRT1 and its downstream SREBP-lipogenesis-cholesterogenesis metabolic pathway in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with miR-132 mimics and inhibitors, and then treated with or without tumor necrosis factor α (TNFα). The effects of miR-132 on pro-inflammatory processes, proliferation and apoptosis were assessed.

Results

We identified that the relative 3’ UTR luciferase activities of SIRT1 were significantly decreased in miR-132 transfected HUVECs (0.338 ± 0.036) compared to control (P = 0.000). miR-132 inhibited SIRT1 expression of mRNA level in HUVECs (0.53 ± 0.06) (P < 0.01) as well as proteins of SIRT1. mRNA expression and protein levels of SREBP (0.45 ± 0.07), fatty acid synthase (FASN) (0.55 ± 0.09) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) (0.62 ± 0.08) (P < 0.01), which are downstream regulated genes, were reduced in HUVECs by miR-132. MiR-132 promoted pro-inflammatory processes and apoptosis of HUVECs induced by TNF-α, and inhibited its proliferation, viability and migration.

Conclusions

SIRT1 mRNAs are direct targets of miR-132. miR-132 controls lipogenesis and cholesterogenesis in HUVECs by inhibiting SIRT1 and SREBP-1c expression and their downstream regulated genes, including FASN and HMGCR. Inhibition of SIRT1 by miR-132 was associated with lipid metabolism-dependent pro-inflammatory processes in HUVECs. The newly identified miRNA, miR-132 represents a novel targeting mechanism for AS therapy.

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References

  1. Suárez Y, Fernández-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res. 2007;100:1164–73.

    Article  PubMed  Google Scholar 

  2. Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res. 2007;101:59–68.

    Article  CAS  PubMed  Google Scholar 

  3. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A. 2008;105:1516–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Fish JE, Santoro MM, Morton SU, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15:272–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Wang S, Aurora AB, Johnson BA, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–71.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Wang S, Aurora AB, Johnson BA, et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. PNAS. 2005;102:16426–31.

    Article  Google Scholar 

  7. Wayman GA, Davare M, Ando H, et al. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. PNAS. 2008;105:9093–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Cheng HY, Papp JW, Varlamova O, et al. MicroRNA modulation of circadian-clock period and entrainment. Neuron. 2007;54:813–29.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Nudelman AS, DiRocco DP, Lambert TJ, et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus. 2010;20:492–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Strum JC, Johnson JH, Ward J, et al. MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1. Mol Endocrinol. 2009;23:1876–84.

    Article  CAS  PubMed  Google Scholar 

  11. Haigis MC, Guarente LP. Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006;20:2913–21.

    Article  CAS  PubMed  Google Scholar 

  12. Longo VD, Kennedy BK. Sirtuins in aging and age-related disease. Cell. 2006;126:257–68.

    Article  CAS  PubMed  Google Scholar 

  13. Chen ML, Yi L, Jin X, et al. Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway. Autophagy 2013; 9. [Epub ahead of print]

  14. Ma L, Liu X, Zhao Y, Chen B, Li X, Qi R. Ginkgolide B reduces LOX-1 expression by inhibiting Akt phosphorylation and increasing Sirt1Expression in oxidized LDL-stimulated human umbilical vein endothelial cells. PLoS One. 2013;8:e74769.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ponugoti B, Kim DH, Xiao Z, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem. 2010;285:33959–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chen CY, Yi L, Jin X, et al. Delphinidin attenuates stress injury induced by oxidized low-density lipoprotein in human umbilical vein endothelial cells. Chem Biol Interact. 2010;183:105–12.

    Article  CAS  PubMed  Google Scholar 

  17. Dif N, Euthine V, Gonnet E, Laville M, Vidal H, Lefai E. Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs. Biochem J. 2006;400:179–88.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Rome S, Lecomte V, Meugnier E, et al. Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle. Physiol Genomics. 2008;34:327–37.

    Article  CAS  PubMed  Google Scholar 

  19. Fernandez-Hernando C, Suarez Y, Rayner KJ, Moore KJ. MicroRNAs in lipid metabolism. Curr Opin Lipidol. 2011;22:86–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Krutzfeldt J, Stoffel M. MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metab. 2006;4:9–12.

    Article  CAS  PubMed  Google Scholar 

  21. Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012;13:213–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Cozzone D, Debard C, Dif N, et al. Activation of liver X receptors promotes lipid accumulation but does not alter insulin action in human skeletal muscle cells. Diabetologia. 2006;49:990–9.

    Article  CAS  PubMed  Google Scholar 

  23. Ivashchenko CY, Bradley BT, Ao ZH, Leiper J, Vallance P, Johns DG. Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and −2. Am J Physiol Heart Circ Physiol. 2010;298:H251–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet. 1997;349:1436–42.

    Article  CAS  PubMed  Google Scholar 

  25. Maskrey BH, Megson IL, Whitfield PD, Rossi AG. Mechanisms of resolution of inflammation: a focus on cardiovascular disease. Arterioscler Thromb Vasc Biol. 2011;31:1001–6.

    Article  CAS  PubMed  Google Scholar 

  26. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Liu Y, Davidson BP, Yue Q, et al. Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition. Circ Cardiovasc Imaging. 2013;6:74–82.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Tangney CC, Rasmussen HE. Polyphenols, inflammation, and cardiovascular disease. Curr Atheroscler Rep. 2013;15:324.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Quiñones M, Miguel M, Aleixandre A. The polyphenols, naturally occurring compounds with beneficial effects on cardiovascular disease. Nutr Hosp. 2012;27:76–89.

    PubMed  Google Scholar 

  30. Zhang QJ, Wang Z, Chen HZ, et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc Res. 2008;80:191–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Lee J, Kemper JK. Controlling SIRT1 expression by microRNAs in health and metabolic disease. Aging. 2010;2:527–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Guarente L, Picard F. Calorie restriction-the SIR2 connection. Cell. 2005;120:473–82.

    Article  CAS  PubMed  Google Scholar 

  33. Fontana L, Klein S. Aging, adiposity, and calorie restriction. JAMA. 2007;297:986–94.

    Article  CAS  PubMed  Google Scholar 

  34. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004;101:6659–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgement

This work was supported by grants from the National Natural Science Foundation of China (No.30600524, No.81071990 and No.81201758), Science and Technology Planning Project of Guangdong Province (No. 2012A030400055, No. 2010B080701088, No. 2011B080701096 and No. 2011B031800184), Science and Technology projects of Guangzhou (No. 2011 J410010 and No. 2011 J4300066), Program of military scientific research project (No. 06MA301). The study sponsors had no involvement in the study.

Conflict of Interest Statement

All authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Cardiology, The first Affiliated Hospital of Chinese PLA General Hospital, Beijing, 100048, China

    Liwei Zhang, Dangsheng Huang, Qiushuang Wang, Dong Shen, Yumei Wang & Bingyang Chen

  2. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Jinqian Zhang

  3. Department of Cardiology, Division of Medicine, Chinese PLA General Hospital, Beijing, 100853, China

    Luyue Gai

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  1. Liwei Zhang
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  2. Dangsheng Huang
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  3. Qiushuang Wang
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  7. Jinqian Zhang
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Correspondence to Jinqian Zhang or Luyue Gai.

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Zhang, L., Huang, D., Wang, Q. et al. MiR-132 Inhibits Expression of SIRT1 and Induces Pro-inflammatory Processes of Vascular Endothelial Inflammation through Blockade of the SREBP-1c Metabolic Pathway. Cardiovasc Drugs Ther 28, 303–311 (2014). https://doi.org/10.1007/s10557-014-6533-x

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  • DOI: https://doi.org/10.1007/s10557-014-6533-x

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