, Volume 41, Issue 2, pp 400–408 | Cite as

High Glucose Stimulates Expression of MFHAS1 to Mitigate Inflammation via Akt/HO-1 Pathway in Human Umbilical Vein Endothelial Cells

  • Hui-hui Wang
  • Peng-fei Sun
  • Wan-kun Chen
  • Jing Zhong
  • Qi-qing Shi
  • Mei-lin Weng
  • Duan Ma
  • Chang-hong Miao


Hyperglycemia is a highly dangerous factor to various diseases, even resulting in death of people. Inflammation plays a key role in this process. The aim of this study was to explore the role of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) in high-glucose induced inflammation. Our research showed that high glucose stimulated the expression of MFHAS1, and overexpression of MFHAS1 can attenuate high-glucose induced inflammation in endothelial cells by decreasing the secretion of cytokines interleukin-1β (IL-1β), interleukin-1α (IL-1α), adhesion molecule intercellular adhesion molecule-1 (ICAM), interleukin-6 (IL-6), interleukin-8 (IL-8), and chemokine ligand 1 (CXCL-1). Furthermore, we found that MFHAS1 promoted the phosphorylation of Akt and the expression of heme oxygenase-1 (HO-1). Our results indicated that MFHAS1 deadened high-glucose induced inflammation by activating AKT/HO-1 pathway, suggesting that MFHAS1 may act as a new therapeutic target of diabetes mellitus.


high glucose inflammation MFHAS1 AKT HO-1 



This work was supported by the National Natural Science Foundation of China (No. 81372101).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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  1. 1.
    IDF Diabetes Atlas Sixth Edition, International Diabetes Federation 2013.Google Scholar
  2. 2.
    Chang, S.C., and W.V. Yang. 2016. Hyperglycemia, tumorigenesis, and chronic inflammation. Critical Reviews in Oncology/Hematology 108: 146–153.CrossRefPubMedGoogle Scholar
  3. 3.
    Badawi, A., A. Klip, P. Haddad, D.E. Cole, B.G. Bailo, A. El-Sohemy, et al. 2010. Type 2 diabetes mellitus and inflammation: prospects for biomarkers of risk and nutritional intervention. Diabetes, Metabolic Syndrome and Obesity 3: 173–186.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Jung, U.J., and M.S. Choi. 2014. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. International Journal of Molecular Sciences 15: 6184–6223.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Donath, M.Y., and S.E. Shoelson. 2011. Type 2 diabetes as an inflammatory disease. Nature Reviews. Immunology 11: 98–107.CrossRefPubMedGoogle Scholar
  6. 6.
    Gothai, S., P. Ganesan, S.Y. Park, S. Fakurazi, D.K. Choi, and P. Arulselvan. 2016. Natural phyto-bioactive compounds for the treatment of type 2 diabetes: inflammation as a target. Nutrients 8.Google Scholar
  7. 7.
    Dihanich, S. 2012. MASL1: a neglected ROCO protein. Biochemical Society Transactions 40: 1090–1094.CrossRefPubMedGoogle Scholar
  8. 8.
    Ng, A.C., J.M. Eisenberg, R.J. Heath, A. Huett, C.M. Robinson, G.J. Nau, et al. 2011. Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity. Proceedings of the National Academy of Sciences of the United States of America 108 (Suppl 1): 4631–4638.CrossRefPubMedGoogle Scholar
  9. 9.
    Kumkhaek, C., W. Aerbajinai, W. Liu, J. Zhu, N. Uchida, R. Kurlander, et al. 2013. MASL1 induces erythroid differentiation in human erythropoietin-dependent CD34+ cells through the Raf/MEK/ERK pathway. Blood 121: 3216–3227.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Xu, G., L. Feng, P. Song, F. Xu, A. Li, Y. Wang, et al. 2016. Isomeranzin suppresses inflammation by inhibiting M1 macrophage polarization through the NF-kappaB and ERK pathway. International Immunopharmacology 38: 175–185.CrossRefPubMedGoogle Scholar
  11. 11.
    Chen, W., Y. Xu, J. Zhong, H. Wang, M. Weng, Q. Cheng, et al. 2016. MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway. Oncotarget 7: 78726–78735.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhong, J., Q.Q. Shi, M.M. Zhu, J. Shen, H.H. Wang, D. Ma, et al. 2015. MFHAS1 is associated with sepsis and stimulates TLR2/NF-kappaB signaling pathway following negative regulation. PLoS One 10: e0143662.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhong, J., H. Wang, W. Chen, Z. Sun, J. Chen, Y. Xu, et al. 2017. Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways. Cell Death & Disease 8: e2763.CrossRefGoogle Scholar
  14. 14.
    Zhao, X.D., Y.H. Qin, J.X. Ma, W. Dang, M. Wang, X. Zhang, et al. 2013. Influence of intensive insulin therapy on vascular endothelial growth factor in patients with severe trauma. Journal of Huazhong University of Science and Technology. Medical Sciences 33: 107–110.CrossRefGoogle Scholar
  15. 15.
    Wong, T.H., H.A. Chen, R.J. Gau, J.H. Yen, and J.L. Suen. 2016. Heme oxygenase-1-expressing dendritic cells promote Foxp3+ regulatory T cell differentiation and induce less severe airway inflammation in murine models. PLoS One 11: e0168919.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mei, X., H.X. Wang, J.S. Li, X.H. Liu, X.F. Lu, Y. Li, et al. 2017. Dusuqing granules (DSQ) suppress inflammation in Klebsiella pneumonia rat via NF-kappaB/MAPK signaling. BMC Complementary and Alternative Medicine 17: 216.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tang, F., Y. Wang, B.A. Hemmings, C. Ruegg, and G. Xue. 2017. PKB/Akt-dependent regulation of inflammation in cancer. Seminars in Cancer Biology.Google Scholar
  18. 18.
    Calle, M.C., and M.L. Fernandez. 2012. Inflammation and type 2 diabetes. Diabetes & Metabolism 38: 183–191.CrossRefGoogle Scholar
  19. 19.
    Tagawa, H., S. Karnan, Y. Kasugai, S. Tuzuki, R. Suzuki, Y. Hosokawa, et al. 2004. MASL1, a candidate oncogene found in amplification at 8p23.1, is translocated in immunoblastic B-cell lymphoma cell line OCI-LY8. Oncogene 23: 2576–2581.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhao, M.X., B. Zhou, L. Ling, X.Q. Xiong, F. Zhang, Q. Chen, et al. 2017. Salusin-beta contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death & Disease 8: e2690.CrossRefGoogle Scholar
  21. 21.
    Eriksson, L., and T. Nystrom. 2015. Antidiabetic agents and endothelial dysfunction—beyond glucose control. Basic & Clinical Pharmacology & Toxicology 117: 15–25.CrossRefGoogle Scholar
  22. 22.
    Pradhan, A.D., J.E. Manson, N. Rifai, J.E. Buring, and P.M. Ridker. 2001. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Journal of the American Medical Association 286: 327–334.CrossRefPubMedGoogle Scholar
  23. 23.
    Maines, M.D. 1988. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. The FASEB Journal 2: 2557–2568.CrossRefPubMedGoogle Scholar
  24. 24.
    Yu, W., X. Zhang, H. Wu, Q. Zhou, Z. Wang, R. Liu, et al. 2017, 2017. HO-1 is essential for tetrahydroxystilbene glucoside mediated mitochondrial biogenesis and anti-inflammation process in LPS-treated RAW264.7 macrophages. Oxidative Medicine and Cellular Longevity: 1818575.Google Scholar
  25. 25.
    Ryter, S.W., J. Alam, and A.M. Choi. 2006. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiological Reviews 86: 583–650.CrossRefPubMedGoogle Scholar
  26. 26.
    Steinberg, G.R., and J.D. Schertzer. 2014. AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunology and Cell Biology 92: 340–345.CrossRefPubMedGoogle Scholar
  27. 27.
    Xu, L., J. Zhu, W. Yin, and X. Ding. 2015. Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt in diabetes rat. International Journal of Clinical and Experimental Pathology 8: 6083–6094.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Rogers, L.J., A.G. Basnakian, M.S. Orloff, B. Ning, A. Yao-Borengasser, V. Raj, et al. 2016. 2-Amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) induces gene expression changes in JAK/STAT and MAPK pathways related to inflammation, diabetes and cancer. Nutrition & Metabolism (London) 13: 54.CrossRefGoogle Scholar
  29. 29.
    Ku, H.C., S.Y. Lee, K.C. Yang, Y.H. Kuo, and M.J. Su. 2016. Modification of caffeic acid with pyrrolidine enhances antioxidant ability by activating AKT/HO-1 pathway in heart. PLoS One 11: e0148545.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017
corrected publication December/2017

Authors and Affiliations

  • Hui-hui Wang
    • 1
  • Peng-fei Sun
    • 1
  • Wan-kun Chen
    • 1
  • Jing Zhong
    • 1
  • Qi-qing Shi
    • 2
  • Mei-lin Weng
    • 1
  • Duan Ma
    • 3
  • Chang-hong Miao
    • 1
  1. 1.Department of AnesthesiologyFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Children’s Hospital of Fudan UniversityShanghaiChina
  3. 3.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Collaborative Innovation Center of Genetics and Development, Institute of Biomedical Sciences, School of Basic Medical SciencesFudan UniversityShanghaiChina

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