Skip to main content
SpringerLink
Log in

Globular CTRP9 inhibits oxLDL-induced inflammatory response in RAW 264.7 macrophages via AMPK activation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

C1q-TNF-related protein-9 (CTRP9) is increasingly recognized as a promising cardioprotective adipocytokine, which regulates biological processes like vascular relaxation, proliferation, apoptosis, and inflammation. We recently showed that CTRP9 enhanced carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. However, the underlying molecular mechanism of CTRP9 on anti-inflammatory response in macrophages still remains unclear. We demonstrated that globular CTRP9 (gCTRP9) significantly reduced oxidized low-density lipoprotein (oxLDL)-induced tumor necrosis factor alpha and monocyte chemoattractant protein 1 expression by suppressing nuclear factor-κB phosphorylation and nuclear translocation in RAW 264.7 macrophages. Treatment with gCTRP9 strikingly increased the level of phosphorylated adenosine monophosphate-activated protein kinase (AMPK). AMPK inhibitor abolished the anti-inflammatory effects of gCTRP9. Moreover, gCTRP9 increased the expression of adiponectin receptor 1 (AdipoR1). Downregulation of AdipoR1 by siRNA could abrogate the activation of AMPK and the anti-inflammatory effects of gCTRP9. These results suggested that gCTRP9 protected RAW 264.7 macrophages from oxLDL via AMPK activation in an AdipoR1 dependent fashion.

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. Ross R (1999) Atherosclerosis is an inflammatory disease. Am Heart J 138:S419–S420

    Article  CAS  PubMed  Google Scholar 

  2. Stoll G, Bendszus M (2006) Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37:1923–1932

    Article  CAS  PubMed  Google Scholar 

  3. Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hilgendorf I, Swirski FK, Robbins CS (2015) Monocyte fate in atherosclerosis. Arterioscler Thromb Vasc Biol 35:272–279

    Article  CAS  PubMed  Google Scholar 

  5. Maiolino G, Rossitto G, Caielli P, Bisogni V, Rossi GP, Calo LA (2013) The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm 2013:714653

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lage R, Dieguez C, Vidal-Puig A, Lopez M (2008) AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 14:539–549

    Article  CAS  PubMed  Google Scholar 

  7. Fullerton MD, Steinberg GR, Schertzer JD (2013) Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol Cell Endocrinol 366:224–234

    Article  CAS  PubMed  Google Scholar 

  8. Ewart MA, Kennedy S (2011) AMPK and vasculoprotection. Pharmacol Ther 131:242–253

    Article  CAS  PubMed  Google Scholar 

  9. Steinberg GR, Schertzer JD (2014) AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunol Cell Biol 92:340–345

    Article  CAS  PubMed  Google Scholar 

  10. Yi CO, Jeon BT, Shin HJ, Jeong EA, Chang KC, Lee JE, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS (2011) Resveratrol activates AMPK and suppresses LPS-induced NF-kappaB-dependent COX-2 activation in RAW 264.7 macrophage cells. Anat Cell Biol 44:194–203

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yuan Y, Lau WB, Su H, Sun Y, Yi W, Du Y, Christopher T, Lopez B, Wang Y, Ma XL (2015) C1q-TNF-related protein-9, a novel cardioprotetcive cardiokine, requires proteolytic cleavage to generate a biologically active globular domain isoform. Am J Physiol Endocrinol Metab 308:E891–E898

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zheng Q, Yuan Y, Yi W, Lau WB, Wang Y, Wang X, Sun Y, Lopez BL, Christopher TA, Peterson JM, Wong GW, Yu S, Yi D, Ma XL (2011) C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol 31:2616–2623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kambara T, Ohashi K, Shibata R, Ogura Y, Maruyama S, Enomoto T, Uemura Y, Shimizu Y, Yuasa D, Matsuo K, Miyabe M, Kataoka Y, Murohara T, Ouchi N (2012) CTRP9 protein protects against myocardial injury following ischemia-reperfusion through AMP-activated protein kinase (AMPK)-dependent mechanism. J Biol Chem 287:18965–18973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Uemura Y, Shibata R, Ohashi K, Enomoto T, Kambara T, Yamamoto T, Ogura Y, Yuasa D, Joki Y, Matsuo K, Miyabe M, Kataoka Y, Murohara T, Ouchi N (2013) Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J 27:25–33

    Article  CAS  PubMed  Google Scholar 

  15. Hardie DG, Sakamoto K (2006) AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 21:48–60

    Article  CAS  Google Scholar 

  16. Jung CH, Lee MJ, Kang YM, Lee Y, Seol SM, Yoon HK, Kang SW, Lee WJ, Park JY (2015) C1q/TNF-related protein-9 inhibits cytokine-induced vascular inflammation and leukocyte adhesiveness via AMP-activated protein kinase activation in endothelial cells. Mol Cell Endocrinol 419:235–243

    Article  PubMed  Google Scholar 

  17. Kambara T, Shibata R, Ohashi K, Matsuo K, Hiramatsu-Ito M, Enomoto T, Yuasa D, Ito M, Hayakawa S, Ogawa H, Aprahamian T, Walsh K, Murohara T, Ouchi N (2015) C1q/tumor necrosis factor-related protein 9 protects against acute myocardial injury through an Adiponectin receptor I-AMPK-dependent mechanism. Mol Cell Biol 35:2173–2185

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang J, Hang T, Cheng XM, Li DM, Zhang QG, Wang LJ, Peng YP, Gong JB (2015) Associations of C1q/TNF-related protein-9 levels in serum and epicardial adipose tissue with coronary Atherosclerosis in humans. Biomed Res Int 2015:971683

    PubMed  PubMed Central  Google Scholar 

  19. Li J, Zhang P, Li T, Liu Y, Zhu Q, Chen T, Liu T, Huang C, Zhang J, Zhang Y, Guo Y (2015) CTRP9 enhances carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. Biochem Biophys Res Commun 458:890–895

    Article  CAS  PubMed  Google Scholar 

  20. Sen R, Smale ST (2010) Selectivity of the NF-{kappa}B response. Cold Spring Harb Perspect Biol 2:a000257

    Article  PubMed  PubMed Central  Google Scholar 

  21. Du J, Huang Y, Yan H, Zhang Q, Zhao M, Zhu M, Liu J, Chen SX, Bu D, Tang C, Jin H (2014) Hydrogen sulfide suppresses oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 generation from macrophages via the nuclear factor kappaB (NF-kappaB) pathway. J Biol Chem 289:9741–9753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamaguchi N, Argueta JG, Masuhiro Y, Kagishita M, Nonaka K, Saito T, Hanazawa S, Yamashita Y (2005) Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett 579:6821–6826

    Article  CAS  PubMed  Google Scholar 

  23. Yamaguchi N, Kukita T, Li YJ, Kamio N, Fukumoto S, Nonaka K, Ninomiya Y, Hanazawa S, Yamashita Y (2008) Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Lett 582:451–456

    Article  CAS  PubMed  Google Scholar 

  24. Capeau J (2007) The story of adiponectin and its receptors AdipoR1 and R2: to follow. J Hepatol 47:736–738

    Article  CAS  PubMed  Google Scholar 

  25. Gleissner CA, Leitinger N, Ley K (2007) Effects of native and modified low-density lipoproteins on monocyte recruitment in atherosclerosis. Hypertension 50:276–283

    Article  CAS  PubMed  Google Scholar 

  26. Pateras I, Giaginis C, Tsigris C, Patsouris E, Theocharis S (2014) NF-kappaB signaling at the crossroads of inflammation and atherogenesis: searching for new therapeutic links. Expert Opin Ther Targets 18:1089–1101

    Article  CAS  PubMed  Google Scholar 

  27. McKellar GE, McCarey DW, Sattar N, McInnes IB (2009) Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol 6:410–417

    Article  CAS  PubMed  Google Scholar 

  28. Boyle JJ, Weissberg PL, Bennett MR (2003) Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol 23:1553–1558

    Article  CAS  PubMed  Google Scholar 

  29. Lin J, Kakkar V, Lu X (2014) Impact of MCP-1 in atherosclerosis. Curr Pharm Des 20:4580–4588

    Article  CAS  PubMed  Google Scholar 

  30. Salt IP, Palmer TM (2012) Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin Investig Drugs 21:1155–1167

    Article  CAS  PubMed  Google Scholar 

  31. Salminen A, Hyttinen JM, Kaarniranta K (2011) AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl) 89:667–676

    Article  CAS  Google Scholar 

  32. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Ge G, Spooner E, Hug C, Gimeno R, Lodish HF (2009) Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. FASEB J 23:241–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T (2014) Adiponectin receptors: a review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab 28:15–23

    Article  CAS  PubMed  Google Scholar 

  34. Takeuchi S, Wada K, Uozumi Y, Otani N, Osada H, Nagatani K, Mori K (2013) Adiponectin receptor 1 expression is associated with carotid plaque stability. Neurol India 61:249–253

    Article  PubMed  Google Scholar 

  35. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332–339

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants of the National Natural Science Foundation of China (No. 81350025) and Department of Science and Technology of Shandong Province (2014GSF118020).

Author information

Authors and Affiliations

  1. Department of Cardiology, Qilu Hospital of Shandong University, 107 Wen Hua Xi Road, Jinan, 250012, Shandong Province, China

    Peng Zhang, Chengmin Huang, Jun Li, Tingting Li, Na Li, Qing Zhu & Yuan Guo

  2. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China

    Peng Zhang, Chengmin Huang, Jun Li, Tingting Li, Haipeng Guo, Tianjiao Liu, Na Li, Qing Zhu & Yuan Guo

  3. Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China

    Haipeng Guo

Authors
  1. Peng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chengmin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tingting Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haipeng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tianjiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Na Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuan Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuan Guo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, P., Huang, C., Li, J. et al. Globular CTRP9 inhibits oxLDL-induced inflammatory response in RAW 264.7 macrophages via AMPK activation. Mol Cell Biochem 417, 67–74 (2016). https://doi.org/10.1007/s11010-016-2714-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-016-2714-1

Keywords

Search

Navigation