Skip to main content

Advertisement

SpringerLink
Log in

MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-κB signaling pathway

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and pro-fibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II-induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subcutaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the AT1 receptor. Finally, we demonstrated the direct interaction between Ang II and MD2 protein via hydrogen bonds on Arg-90, Glu-92, and Asp-100. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ben Haij N, Leghmari K, Planes R, Thieblemont N, Bahraoui E (2013) HIV-1 Tat protein binds to TLR4–MD2 and signals to induce TNF-alpha and IL-10. Retrovirology. doi:10.1186/1742-4690-10-123

    PubMed  PubMed Central  Google Scholar 

  2. Braunwald E (2015) The war against heart failure: the Lancet lecture. Lancet 385:812–824. doi:10.1016/s0140-6736(14)61889-4

    Article  PubMed  Google Scholar 

  3. Cardinale JP, Sriramula S, Mariappan N, Agarwal D, Francis J (2012) Angiotensin II-induced hypertension is modulated by nuclear factor-kappaBin the paraventricular nucleus. Hypertension 59:113–121. doi:10.1161/HYPERTENSIONAHA.111.182154

    Article  CAS  PubMed  Google Scholar 

  4. Choi SH, Kim J, Gonen A, Viriyakosol S, Miller YI (2016) MD-2 binds cholesterol. Biochem Biophys Res Commun 470:877–880. doi:10.1016/j.bbrc.2016.01.126

    Article  CAS  PubMed  Google Scholar 

  5. Dange RB, Agarwal D, Masson GS, Vila J, Wilson B, Nair A, Francis J (2014) Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension. Cardiovasc Res 103:17–27. doi:10.1093/cvr/cvu067

    Article  CAS  PubMed  Google Scholar 

  6. Dassanayaka S, Jones SP (2015) Recent developments in heart failure. Circ Res 117:e58–e63. doi:10.1161/circresaha.115.305765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, Tanimura N, Akashi-Takamura S, Miyake K, Maru Y (2013) Serum amyloid A3 binds MD-2 to activate p38 and NF-kappa B pathways in a MyD88-dependent manner. J Immunol 191:1856–1864. doi:10.4049/jimmunol.1201996

    Article  CAS  PubMed  Google Scholar 

  8. Duan G, Zhu J, Xu J, Liu Y (2014) Targeting myeloid differentiation 2 for treatment of sepsis. Front Biosci Landmark 19:904–915. doi:10.2741/4256

    Article  Google Scholar 

  9. Echem C, Bomfim GF, Ceravolo GS, Oliveira MA, Santos-Eichler RA, Bechara LR, Veras MM, Saldiva PH, Ferreira JC, Akamine EH, Fortes ZB, Dantas AP, de Carvalho MH (2015) Anti-toll like receptor 4 (TLR4) therapy diminishes cardiac remodeling regardless of changes in blood pressure in spontaneously hypertensive rats (SHR). Int J Cardiol 187:243–245. doi:10.1016/j.ijcard.2015.03.190

    Article  PubMed  Google Scholar 

  10. Fan D, Takawale A, Basu R, Patel V, Lee J, Kandalam V, Wang X, Oudit GY, Kassiri Z (2014) Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction. Cardiovasc Res 103:268–280. doi:10.1093/cvr/cvu072

    Article  CAS  PubMed  Google Scholar 

  11. Frieler RA, Mortensen RM (2015) Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation 131:1019–1030. doi:10.1161/circulationaha.114.008788

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hedayat M, Netea MG, Rezaei N (2011) Targeting of Toll-like receptors: a decade of progress in combating infectious diseases. Lancet Infect Dis 11:702–712. doi:10.1016/S1473-3099(11)70099-8

    Article  CAS  PubMed  Google Scholar 

  13. Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L (2014) Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 383:1933–1943. doi:10.1016/s0140-6736(14)60107-0

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ji Y, Liu J, Wang Z, Liu N (2009) Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell Physiol Biochem 23:265–276. doi:10.1159/000218173

    Article  CAS  PubMed  Google Scholar 

  15. Ji Y, Liu J, Wang Z, Liu N, Gou W (2009) PPARgamma agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway. Lab Invest 89:887–902. doi:10.1038/labinvest.2009.45

    Article  CAS  PubMed  Google Scholar 

  16. Jiang D-S, Zhang X-F, Gao L, Zong J, Zhou H, Liu Y, Zhang Y, Bian Z-Y, Zhu L-H, Fan G-C, Zhang X-D, Li H (2014) Signal regulatory protein-alpha protects against cardiac hypertrophy via the disruption of toll-like receptor 4 signaling. Hypertension 63:96–104. doi:10.1161/hypertensionaha.113.01506

    Article  CAS  PubMed  Google Scholar 

  17. Kurdi M, Booz GW (2011) New take on the role of angiotensin II in cardiac hypertrophy and fibrosis. Hypertension 57:1034–1038. doi:10.1161/hypertensionaha.111.172700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li YS, Ni SY, Meng Y, Shi XL, Zhao XW, Luo HH, Li X (2013) Angiotensin II facilitates fibrogenic effect of TGF-beta1 through enhancing the down-regulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II. PLoS One 8:e76289. doi:10.1371/journal.pone.0076289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mancek-Keber M, Jerala R (2006) Structural similarity between the hydrophobic fluorescent probe and lipid A as a ligand of MD-2. Faseb J 20:1836–1842. doi:10.1096/fj.06-5862com

    Article  CAS  PubMed  Google Scholar 

  20. Matsuda S, Umemoto S, Yoshimura K, Itoh S, Murata T, Fukai T, Matsuzaki M (2015) Angiotensin. Activates MCP-1 and induces cardiac hypertrophy and dysfunction via toll-like receptor 4. J Atheroscler Thromb 22:833–844. doi:10.5551/jat.27292

    Article  CAS  PubMed  Google Scholar 

  21. Matsui Y, Jia N, Okamoto H, Kon S, Onozuka H, Akino M, Liu LZ, Morimoto J, Rittling SR, Denhardt D, Kitabatake A, Uede T (2004) Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension 43:1195–1201. doi:10.1161/01.HYP.0000128621.68160.dd

    Article  CAS  PubMed  Google Scholar 

  22. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. doi:10.1002/jcc.21256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, Kitamura T, Kosugi A, Kimoto M, Miyake K (2002) Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 3:667–672. doi:10.1038/ni809

    CAS  PubMed  Google Scholar 

  24. Nair AR, Ebenezer PJ, Saini Y, Francis J (2015) Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1–TLR4 signaling in rat tubulo-epithelial cells. Exp Cell Res 335:238–247. doi:10.1016/j.yexcr.2015.05.011

    Article  CAS  PubMed  Google Scholar 

  25. Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T, Namba M (1998) Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation 98:794–799. doi:10.1161/01.CIR.98.8.794

    Article  CAS  PubMed  Google Scholar 

  26. Niu J, Jin Z, Kim H, Kolattukudy PE (2015) MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-kappaB activation and suppressing inflammation-associated microRNA expression. Basic Res Cardiol 110:26. doi:10.1007/s00395-015-0483-8

    Article  PubMed  Google Scholar 

  27. Ohto U, Fukase K, Miyake K, Satow Y (2007) Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316:1632–1634. doi:10.1126/science.1139111

    Article  CAS  PubMed  Google Scholar 

  28. Paulus WJ, Tschoepe C (2013) A novel paradigm for heart failure with preserved ejection fraction comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62:263–271. doi:10.1016/j.jacc.2013.02.092

    Article  PubMed  Google Scholar 

  29. Peng JF, Gurantz D, Tran V, Cowling RT, Greenberg BH (2002) Tumor necrosis factor-alpha-induced AT(1) receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis. Circ Res 91:1119–1126. doi:10.1161/01.res.0000047090.08299.d5

    Article  CAS  PubMed  Google Scholar 

  30. Roh E, Lee HS, Kwak JA, Hong JT, Nam SY, Jung SH, Lee JY, Kim ND, Han SB, Kim Y (2011) MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity. J Infect Dis 203:1012–1020. doi:10.1093/infdis/jiq155

    Article  CAS  PubMed  Google Scholar 

  31. Shah AM (2013) Ventricular remodeling in heart failure with preserved ejection fraction. Curr Heart Fail Rep 10:341–349. doi:10.1007/s11897-013-0166-4

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78:539–552. doi:10.1016/j.bcp.2009.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sriramula S, Haque M, Majid DSA, Francis J (2008) Involvement of tumor necrosis factor-alpha in angiotensin II-mediated effects on salt appetite, hypertension, and cardiac hypertrophy. Hypertension 51:1345–1351. doi:10.1161/hypertensionaha.107.102152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Timmers L, Sluijter JPG, van Keulen JK, Hoefer IE, Nederhoff MGJ, Goumans MJ, Doevendans PA, van Echteld CJA, Joles JA, Quax PH, Piek JJ, Pasterkamp G, de Kleijn DPV (2008) Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res 102:257–264. doi:10.1161/circresaha.107.158220

    Article  CAS  PubMed  Google Scholar 

  35. Wang L, Li YL, Zhang CC, Cui W, Wang X, Xia Y, Du J, Li HH (2014) Inhibition of toll-like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation. Cardiovasc Res 101:383–392. doi:10.1093/cvr/cvt258

    Article  CAS  PubMed  Google Scholar 

  36. Wang Y, Shan X, Chen G, Jiang L, Wang Z, Fang Q, Liu X, Wang J, Zhang Y, Wu W, Liang G (2015) MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis. Br J Pharmacol 172:4391–4405. doi:10.1111/bph.13221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wollert KC, Drexler H (1999) The renin-angiotensin system and experimental heart failure. Cardiovasc Res 43:838–849. doi:10.1016/s0008-6363(99)00145-5

    Article  CAS  PubMed  Google Scholar 

  38. Yang H, Wang H, Ju Z, Ragab AA, Lundback P, Long W, Valdes-Ferrer SI, He M, Pribis JP, Li J, Lu B, Gero D, Szabo C, Antoine DJ, Harris HE, Golenbock DT, Meng J, Roth J, Chavan SS, Andersson U, Billiar TR, Tracey KJ, Al-Abed Y (2015) MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. J Exp Med 212:5–14. doi:10.1084/jem.20141318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang L, Zou X, Liang Q, Chen H, Feng J, Yan L, Wang Z, Zhou D, Li S, Ya S, Zheng Z (2007) Sodium tanshinone IIA sulfonate depresses angiotensin II-induced cardiomyocyte hypertrophy through MEK/ERK pathway. Exp Mol Med 39:65–73. doi:10.1038/emm.2007.8

    Article  CAS  PubMed  Google Scholar 

  40. Zablocki D, Sadoshima J (2013) Solving the cardiac hypertrophy riddle: the angiotensin II-mechanical stress connection. Circ Res 113:1192–1195. doi:10.1161/circresaha.113.302501

    Article  CAS  PubMed  Google Scholar 

  41. Zhou G, Li X, Hein DW, Xiang X, Marshall JP, Prabhu SD, Cai L (2008) Metallothionein suppresses angiotensin II-induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart. J Am Coll Cardiol 52:655–666. doi:10.1016/j.jacc.2008.05.019

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (81622043, 81470565, 81503123, 81670244, and 81302821), and Natural Science Funding of Zhejiang Province (LR16H310001).

Author information

Author notes

    Authors and Affiliations

    1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

      Jibo Han, Yali Zhang, Yuanyuan Qian, Yong Pan, Zheng Xu, Bin Bai & Guang Liang

    2. Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Jibo Han, Shengban You & Weijian Huang

    3. Department of Ultrasonography, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Chunpeng Zou

    4. Department of Oral Prophylaxis and Hygiene, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, China

      Liqin Mei

    Authors
    1. Jibo Han
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Chunpeng Zou
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Liqin Mei
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yali Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yuanyuan Qian
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shengban You
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yong Pan
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Zheng Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Bin Bai
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Weijian Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Guang Liang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Weijian Huang or Guang Liang.

    Ethics declarations

    Conflict of interest

    All the authors declare no competing financial interest.

    Additional information

    J. Han and C. Zou contribute equally to this paper.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 2900 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Han, J., Zou, C., Mei, L. et al. MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-κB signaling pathway. Basic Res Cardiol 112, 9 (2017). https://doi.org/10.1007/s00395-016-0599-5

    Download citation

    • Received:

    • Accepted:

    • Published:

    • DOI: https://doi.org/10.1007/s00395-016-0599-5

    Keywords

    Search

    Navigation