Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Tumor necrosis factor-related apoptosis-inducing ligand regulate the accumulation of extracelluar matrix in pulmonary artery by activating the phosphorylation of Smad2/3

Cardiovascular Department for Gerontism, The Second Hospital of Anhui Medical University, Hefei 230601, China

These authors contributed equally to this work.

Special Issues: Advanced Big Data Analysis for Precision Medicine

Introduction: Previous studies have found that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was involved in the progression of pulmonary hypertension (PH), and TRAIL knocking (KO) has an inhibitory effect on PH, but its mechanism is not completely clear. Methods: The effects of TRAIL on the accumulation of extracelluar matrix (ECM), which is one of the most important processes of vascular remodeling, were observed in mice and isolated pulmonary artery smooth muscle cells (PASMCs). In vivo, mice were divided into four groups: Control group (n = 5), hypoxia-induced PH mice group (n = 8), anti-TRAIL antibody (TRAIL-Ab) treatment group (n = 8) and IgG antibody (IgG) group (n = 8). The effects of TRAIL-Ab on ECM expression in hypoxic induced PH were researched; in vivo, PASMCs were divided into three groups: Control group, hypoxia-induced group, TRAIL-Ab group. Expressions of p-Smad2/3 and p-Smad1/5/8 were compared among the three groups. Results: Hypoxia-induced PH mice had significant increases in right ventricle systolic pressure (RVSP) (P < 0.001), right ventricular hypertrophy (RVH) (P = 0.007), vascular stenosis (P < 0.001) compared with controls. Mice with anti-TRAIL antibody had lower levels in RVSP (P < 0.001), RVH (P < 0.001), vascular stenosis (P < 0.001) than PH mice. Besides, the TRAIL-Ab significantly inhibited the phosphorylation of Smad2/3 compared with hypoxia-induced group. Conclusion: TRAIL regulates the accumulation of ECM in pulmonary artery by activating pSmad2/3.
  Article Metrics

Keywords tumor necrosis factor-related apoptosis-inducing ligand; extracelluar matrix; pSmad2/3; pulmonary hypertension; mechanism

Citation: Erli Yang, Xiaobei Zhang, Qiangsheng Chen, Chandong Ding. Tumor necrosis factor-related apoptosis-inducing ligand regulate the accumulation of extracelluar matrix in pulmonary artery by activating the phosphorylation of Smad2/3. Mathematical Biosciences and Engineering, 2020, 17(2): 1372-1380. doi: 10.3934/mbe.2020069


  • 1. A. B. Waxman and R. T. Zamanian, Pulmonary arterial hypertension: New insights into the optimal role of current and emerging prostacyclin therapies, Am. J. Cardiol., 111 (2013), 1A-16A.
  • 2. L. J. Rubin, Primary pulmonary hypertension, N. Engl. J. Med., 336 (1997), 111-117.
  • 3. J. R. Runo and J. E. Loyd, Primary pulmonary hypertension, Lancet, 361 (2003), 1533-1544.
  • 4. J. Hänze, N. Weissmann, F. Grimminger, et al., Cellular and molecular mechanisms of hypoxia inducible factor driven vascular remodeling, Thromb. Haemostasis, 97 (2007), 774-787.
  • 5. P. M. Hassoun, Deciphering the "matrix" in pulmonary vascular remodeling, Eur. Respir. J., 25 (2005), 778-779.
  • 6. E. Arciniegas, M. G. Frid, I. S. Douglas, et al., Perspectives on endothelial to mesenchymal transition: Potential contribution to vascular remodeling in chronic pulmonary hypertension, Am. J. Physiol. Lung Cell. Mol. Physiol., 293 (2007), L1-L8.
  • 7. G. Burgstaller, B. Oehrle, M. Gerckens, et al., The instructive extracellular matrix of the lung: Basic composition and alterations in chronic lung disease, Eur. Respir. J., 50 (2017), 1601805.
  • 8. V. Jurisic, T. Srdic-Rajic, G. Konjevic, et al., TNF-α induced apoptosis is accompanied with rapid CD30 and slower CD45 shedding from K-562 cells, J. Membr. Biol., 293 (2011), 115-122.
  • 9. V. Jurisic, T. Terzic, S. Colic, et al., The concentration of TNF-α correlate with number of inflammatory cells and degree of vascularization in radicular cysts, Oral Dis., 14 (2008), 600-605.
  • 10. A. Lawrie, A. G. Hameed, J. Chamberlain, et al., Paigen diet-fed apolipoprotein E knockout mice develop severe pulmonary hypertension in an interleukin-1-dependent manner, Am. J. Pathol., 179 (2011), 1693-1705.
  • 11. N. M. Robertson, M. Rosemiller, R. G. Lindemeyer, et al., TRAIL in the Airways, Vitam. Horm., 67 (2004), 149-167.
  • 12. B. R. Gochuico, J. Zhang, B. Y. Ma, et al., TRAIL expression in vascular smooth muscle, Am. J. Physiol. Lung Cell. Mol. Physiol., 278 (2000), L1045-L1050.
  • 13. A. Lawrie, E. Waterman, M. Southwood, et al., Evidence of a role for osteoprotrgerin in the pathogenesis of pulmonary arterial hypertension, Am. J. Pathol., 172 (2008), 256-264.
  • 14. X. D. Zhang, T. Nguyen, W. D. Thomas, et al., Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types, FEBS Lett., 482 (2000), 193-199.
  • 15. R. Di Pietro, M. A. Mariggio, S. Guarnieri, et al., Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Regulates Endothelial Nitric Oxide Synthase (eNOS) Activity and Its Localization Within the Human Vein Endothelial Cells (HUVEC) in Culture, J. Cell. Biochem., 97 (2006), 782-794.    
  • 16. H. Liu, E. Yang, X. Lu, et al., Serum levels of tumor necrosis factor-related apoptosis-inducing ligand correlate with the severity of pulmonary hypertension, Pulm. Pharmacol. Ther., 33 (2015), 39-46.
  • 17. A. G. Hameed, N. D. Arnold, J. Chamberlain, et al., Inhibition of tumor necrosis factor-related Apoptosis-inducing ligand reverses experimental pulmonary hypertension, J. Exp. Med., 216 (2012), 1919-1935.
  • 18. G. S. Wu, TRAIL as a target in anti-cancer therapy, Cancer Lett., 285 (2009), 1-5.
  • 19. S. R. Wiley, K. Schooley, P. J. Smolak, et al., Identification and characterization of a new member of the TNF family that induces apoptosis, Immunity, 3 (1995), 673-682.
  • 20. H. B. Schiller, I. E. Fernandez, G. Burgstaller, et al., Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair, Mol. Syst. Biol., 11 (2015), 819.
  • 21. H. N. LeBlanc, A. Ashkenazi, Apo2L/TRAIL and its death and decoy receptors, Cell Death Differ., 10 (2003), 66-75.
  • 22. P. Secchiero, F. Corallini, M. G. di Iasio, et al., TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release, Blood, 105 (2005), 3413-3419.    
  • 23. A. Almasan and A. Ashkenazi, Apo2L/TRAIL: Apoptosis signaling, biology, and potential for cancer therapy, Cytokine Growth Factor Rev., 14 (2003), 337-348.
  • 24. P. Secchiero, A. Gonelli, E. Carnevale, et al., TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and Erk pathway, Circulation, 107 (2003), 2250-2256.
  • 25. J. P. Sheridan, S. A. Marsters, R. M. Pitti, et al., Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors, Science, 277 (1997), 818-821.
  • 26. C. Falschlehner, C. H. Emmerich, B. Gerlach, et al., TRAIL signalling: Decisions between life and death, Int. J. Biochem. Cell Biol., 39 (2007), 1462-1475.
  • 27. S. M. Mariani and P. H. Krammer, Differential regulation of TRAIL and CD95 ligand in transformed cells of the T and B lymphocyte lineage, Eur. J. Immunol., 28 (1998), 973-982.
  • 28. P. Secchiero, R. Candido, F. Corallini, et al., Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice, Circulation, 114 (2006), 1522-1530.    
  • 29. X. Liu, V. R. Winrow, M. Horrocks, et al., Differential expression of TRAIL and its receptors relative to calcification in AAA, Biochem. Biophys. Res. Commun., 358 (2007), 18-23.
  • 30. S. P. Cartland, S. W. Genner, A. Zahoor, et al., Comparative Evaluation of TRAIL, FGF-2 and VEGF-A-Induced Angiogenesis In Vitro and In Vivo, Int. J. Mol. Sci., 17 (2016), 2025.
  • 31. J. R. Jackson, M. P. Seed, C. H. Kircher, et al., The codependence of angiogenesis and chronic inflammation, FASEB J., 11 (1997), 457-465.
  • 32. A. A. Eddy and C. M. Giachelli, Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria, Kidney Int., 47 (1995), 1546-1557.
  • 33. F. Verrecchia, and A. Mauviel, Transforming growth factor-beta signaling through the Smad pathway: Role in extracellular matrix gene expression and regulation, J. Invest. Dermatol., 118 (2002), 211-215.
  • 34. A. Leask, D. J. Abraham, D. R. Finlay, et al., Dysregulation of transforming growth factor beta signaling in scleroderma: Overexpression of endoglin in cutaneous scleroderma fibroblasts, Arthritis Rheumatol., 46 (2002), 1857-1865.
  • 35. K. J. Gordon, M. Dong, E. M. Chislock, et al., Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression, Carcinogenesis, 29 (2008), 252-262.
  • 36. G. Sánchez-Duffhues, C. Hiepen, P. Knaus, et al., Bone morphogenetic protein signaling in bone homeostasis, Bone, 80 (2015), 43-59.
  • 37. A. G. de Vinuesa, S. Abdelilah-Seyfried, P. Knaus, et al., BMP signaling in vascular biology and dysfunction, Cytokine Growth Factor Rev., 27 (2016), 65-79.
  • 38. C. H. Heldin, K. Miyazono and P. Ten Dijke, TGF-beta signaling from cell membrane to nucleus through SMAD proteins, Nature, 390 (1997), 465-471.
  • 39. K. Miyazono, K. Kusanagi and H. Inoue, Divergence and convergence of TGF-beta/BMP signaling, J. Cell. Physiol., 187 (2001), 265-276.
  • 40. H. Yagita, K. Takeda, Y. Hayakawa, et al., TRAIL and its receptors as targets for cancer therapy, Cancer Sci., 95 (2004), 777-783..
  • 41. T. Kunieda, N. Nakanishi, T. Satoh, et al., Prognoses of primary pulmonary hypertension and chronic majorvessel thromboembolic pulmonary hypertension determined from cumulative survival curves, Intern. Med., 38 (1999), 543-546.


Reader Comments

your name: *   your email: *  

© 2020 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved