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Serum–glucocorticoid-regulated kinase 1 contributes to mechanical stretch-induced inflammatory responses in cardiac fibroblasts

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Abstract

Excessive mechanical stretch induces production of proinflammatory mediators in cardiac fibroblasts, which could act as inflammatory supporter cells in heart failure. Accumulation evidence and our previous studies suggest that serum–glucocorticoid-regulated kinase 1 (SGK1) contributes to cardiac remodeling and fibrosis, development of heart failure. However, the role and mechanism of SGK1 in mechanical stretch-induced inflammation of cardiac fibroblasts remain unclear. Here, cardiac fibroblasts isolated from wild-type (WT) and SGK1 knockout (SGK1−/−) mice were stimulated by 18% cyclic stretch, under static condition as the control. The results showed that mechanical stretch increased SGK1 expression and activation in WT cardiac fibroblasts but not its isoform, SGK2 or SGK3 expression. Bio-Plex array revealed hyperstretch could enhance chemokines release in WT cardiac fibroblasts, but SGK1 knockout significantly attenuated chemokines production through blocking activation of nuclear factor-kappa B (NF-κB). Moreover, supernatants from WT cardiac fibroblasts subjected to hyperstretch promoted macrophage migration, enhanced expression of macrophage-derived profibrotic mediators, whereas supernatants from SGK1 deficiency suppressed these effects. Although SGK1 did not directly affect mechanical stretch-induced myofibroblast differentiation, SGK1 activation of cardiac fibroblasts facilitated myofibroblast differentiation through the upregulation of the profibrotic mediators secreted by macrophages. These results suggest that SGK1 may play a critical role in the inflammatory cascade of cardiac fibroblasts triggered by mechanical stretch; SGK1 could be used as a potential target for treatment of cardiac fibrosis and heart failure.

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Abbreviations

SGK:

Serum–glucocorticoid-regulated kinase

NF-κb:

Nuclear factor-kappa B

ECM:

Extracellular matrix

MCP-1:

Monocyte chemotactic protein 1

MIP-1α:

Macrophage inflammatory protein-1 alpha

MIP-1β:

Macrophage inflammatory protein-1 beta

RANTES:

Regulated upon activation normal T-cell expressed and secreted

CXCL1:

Chemokine (C-X-C motif) ligand 1

TGF-β:

Transforming growth factor-β

IL:

Interleukin

PDGF:

Platelet-derived growth factor

TNF-α:

Tumor necrosis factor-alpha

IFN-γ:

Interferon-γ

IKKα/β:

Inhibitor of κB kinase α/β

IκBα:

Inhibitor of κBα

α-SMA:

α smooth muscle actin

References

  1. Sharma K, Kass DA (2014) Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115:79–96. https://doi.org/10.1161/CIRCRESAHA.115.302922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Oka T, Akazawa H, Naito AT, Komuro I (2014) Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ Res 114:565–571. https://doi.org/10.1161/CIRCRESAHA.114.300507

    Article  PubMed  CAS  Google Scholar 

  3. Anders HJ, Ryu M (2011) Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int 80:915–925. https://doi.org/10.1038/ki.2011.217

    Article  PubMed  CAS  Google Scholar 

  4. van Putten S, Shafieyan Y, Hinz B (2016) Mechanical control of cardiac myofibroblasts. J Mol Cell Cardiol 93:133–142. https://doi.org/10.1016/j.yjmcc.2015.11.025

    Article  PubMed  CAS  Google Scholar 

  5. Yong KW, Li Y, Huang G, Lu TJ, Safwani WK, Pingguan-Murphy B, Xu F (2015) Mechanoregulation of cardiac myofibroblast differentiation: implications for cardiac fibrosis and therapy. Am J Physiol Heart Circ Physiol 309:H532–H542. https://doi.org/10.1152/ajpheart.00299.2015

    Article  PubMed  CAS  Google Scholar 

  6. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschope C (2011) Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail 4:44–52. https://doi.org/10.1161/CIRCHEARTFAILURE.109.931451

    Article  PubMed  Google Scholar 

  7. Kurose H, Mangmool S (2016) Myofibroblasts and inflammatory cells as players of cardiac fibrosis. Arch Pharm Res 39:1100–1113. https://doi.org/10.1007/s12272-016-0809-6

    Article  PubMed  CAS  Google Scholar 

  8. Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC (2016) Cardiac fibrosis: the fibroblast awakens. Circ Res 118:1021–1040. https://doi.org/10.1161/CIRCRESAHA.115.306565

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30:245–257. https://doi.org/10.1055/s-0030-1255354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Glezeva N, Horgan S, Baugh JA (2015) Monocyte and macrophage subsets along the continuum to heart failure: misguided heroes or targetable villains? J Mol Cell Cardiol 89:136–145. https://doi.org/10.1016/j.yjmcc.2015.10.029

    Article  PubMed  CAS  Google Scholar 

  11. Kryczka J, Boncela J (2015) Leukocytes: the double-edged sword in fibrosis. Mediators Inflamm. https://doi.org/10.1155/2015/652035

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hams E, Bermingham R, Fallon PG (2015) Macrophage and innate lymphoid cell interplay in the genesis of fibrosis. Front Immunol 6:597. https://doi.org/10.3389/fimmu.2015.00597

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lindner D, Zietsch C, Tank J, Sossalla S, Fluschnik N, Hinrichs S, Maier L, Poller W, Blankenberg S, Schultheiss HP, Tschope C, Westermann D (2014) Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol 109:428. https://doi.org/10.1007/s00395-014-0428-7

    Article  PubMed  Google Scholar 

  14. Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V (2006) (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev 86:1151–1178. https://doi.org/10.1152/physrev.00050.2005

    Article  PubMed  CAS  Google Scholar 

  15. Lang F, Voelkl J (2013) Therapeutic potential of serum and glucocorticoid inducible kinase inhibition. Expert Opin Investig Drugs 22:701–714. https://doi.org/10.1517/13543784.2013.778971

    Article  PubMed  CAS  Google Scholar 

  16. Cheng J, Wang Y, Ma Y, Chan BT, Yang M, Liang A, Zhang L, Li H, Du J (2010) The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts. Circ Res 107:1265–1274. https://doi.org/10.1161/CIRCRESAHA.110.222588

    Article  PubMed  CAS  Google Scholar 

  17. Feng Y, Wang Q, Wang Y, Yard B, Lang F (2005) SGK1-mediated fibronectin formation in diabetic nephropathy. Cell Physiol Biochem 16:237–244. https://doi.org/10.1159/000089849

    Article  PubMed  CAS  Google Scholar 

  18. Vallon V, Wyatt AW, Klingel K, Huang DY, Hussain A, Berchtold S, Friedrich B, Grahammer F, Belaiba RS, Gorlach A, Wulff P, Daut J, Dalton ND, Ross J Jr, Flogel U, Schrader J, Osswald H, Kandolf R, Kuhl D, Lang F (2006) SGK1-dependent cardiac CTGF formation and fibrosis following DOCA treatment. J Mol Med 84:396–404. https://doi.org/10.1007/s00109-005-0027-z

    Article  PubMed  CAS  Google Scholar 

  19. Waerntges S, Klingel K, Weigert C, Fillon S, Buck M, Schleicher E, Rodemann HP, Knabbe C, Kandolf R, Lang F (2002) Excessive transcription of the human serum and glucocorticoid dependent kinase hSGK1 in lung fibrosis. Cell Physiol Biochem 12:135–142. https://doi.org/10.1159/000063790

    Article  PubMed  CAS  Google Scholar 

  20. Klingel K, Warntges S, Bock J, Wagner CA, Sauter M, Waldegger S, Kandolf R, Lang F (2000) Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. Am J Physiol Gastrointest Liver Physiol 279:G998-G1002

    Article  PubMed  Google Scholar 

  21. Voelkl J, Lin Y, Alesutan I, Ahmed MS, Pasham V, Mia S, Gu S, Feger M, Saxena A, Metzler B, Kuhl D, Pichler BJ, Lang F (2012) Sgk1 sensitivity of Na(+)/H(+) exchanger activity and cardiac remodeling following pressure overload. Basic Res Cardiol 107:236. https://doi.org/10.1007/s00395-011-0236-2

    Article  PubMed  CAS  Google Scholar 

  22. Das S, Aiba T, Rosenberg M, Hessler K, Xiao C, Quintero PA, Ottaviano FG, Knight AC, Graham EL, Bostrom P, Morissette MR, del Monte F, Begley MJ, Cantley LC, Ellinor PT, Tomaselli GF, Rosenzweig A (2012) Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation 126:2208–2219. https://doi.org/10.1161/CIRCULATIONAHA.112.115592

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Yang M, Zheng J, Miao Y, Wang Y, Cui W, Guo J, Qiu S, Han Y, Jia L, Li H, Cheng J, Du J (2012) Serum-glucocorticoid regulated kinase 1 regulates alternatively activated macrophage polarization contributing to angiotensin II-induced inflammation and cardiac fibrosis. Arterioscler Thromb Vasc Biol 32:1675–1686. https://doi.org/10.1161/ATVBAHA.112.248732

    Article  PubMed  CAS  Google Scholar 

  24. Yang M, Shao JH, Miao YJ, Cui W, Qi YF, Han JH, Lin X, Du J (2014) Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization. Cell Death Differ 21:1290–1302. https://doi.org/10.1038/cdd.2014.45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734. https://doi.org/10.1038/nri910

    Article  PubMed  CAS  Google Scholar 

  26. Prante C, Milting H, Kassner A, Farr M, Ambrosius M, Schon S, Seidler DG, Banayosy AE, Korfer R, Kuhn J, Kleesiek K, Gotting C (2007) Transforming growth factor beta1-regulated xylosyltransferase I activity in human cardiac fibroblasts and its impact for myocardial remodeling. J Biol Chem 282:26441–26449. https://doi.org/10.1074/jbc.M702299200

    Article  PubMed  CAS  Google Scholar 

  27. Engebretsen KV, Lunde IG, Strand ME, Waehre A, Sjaastad I, Marstein HS, Skrbic B, Dahl CP, Askevold ET, Christensen G, Bjornstad JL, Tonnessen T (2013) Lumican is increased in experimental and clinical heart failure, and its production by cardiac fibroblasts is induced by mechanical and proinflammatory stimuli. FEBS J 280:2382–2398. https://doi.org/10.1111/febs.12235

    Article  PubMed  CAS  Google Scholar 

  28. Song J, Zhu Y, Li J, Liu J, Gao Y, Ha T, Que L, Liu L, Zhu G, Chen Q, Xu Y, Li C, Li Y (2015) Pellino1-mediated TGF-beta1 synthesis contributes to mechanical stress induced cardiac fibroblast activation. J Mol Cell Cardiol 79:145–156. https://doi.org/10.1016/j.yjmcc.2014.11.006

    Article  PubMed  CAS  Google Scholar 

  29. Herum KM, Lunde IG, Skrbic B, Florholmen G, Behmen D, Sjaastad I, Carlson CR, Gomez MF, Christensen G (2013) Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress. J Mol Cell Cardiol 54:73–81. https://doi.org/10.1016/j.yjmcc.2012.11.006

    Article  PubMed  CAS  Google Scholar 

  30. Suzuki K, Satoh K, Ikeda S, Sunamura S, Otsuki T, Satoh T, Kikuchi N, Omura J, Kurosawa R, Nogi M, Numano K, Sugimura K, Aoki T, Tatebe S, Miyata S, Mukherjee R, Spinale FG, Kadomatsu K, Shimokawa H (2016) Basigin promotes cardiac fibrosis and failure in response to chronic pressure overload in mice. Arterioscler Thromb Vasc Biol 36:636–646. https://doi.org/10.1161/ATVBAHA.115.306686

    Article  PubMed  CAS  Google Scholar 

  31. Baudino TA, Carver W, Giles W, Borg TK (2006) Cardiac fibroblasts: friend or foe? Am J Physiol Heart Circ Physiol 291:H1015–H1026. https://doi.org/10.1152/ajpheart.00023.2006

    Article  PubMed  CAS  Google Scholar 

  32. Aoyama T, Matsui T, Novikov M, Park J, Hemmings B, Rosenzweig A (2005) Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111:1652–1659. https://doi.org/10.1161/01.CIR.0000160352.58142.06

    Article  PubMed  CAS  Google Scholar 

  33. Le Bellego F, Perera H, Plante S, Chakir J, Hamid Q, Ludwig MS (2009) Mechanical strain increases cytokine and chemokine production in bronchial fibroblasts from asthmatic patients. Allergy 64:32–39. https://doi.org/10.1111/j.1398-9995.2008.01814.x

    Article  PubMed  CAS  Google Scholar 

  34. Kunanusornchai W, Muanprasat C, Chatsudthipong V (2016) Adenosine monophosphate-activated protein kinase activation and suppression of inflammatory response by cell stretching in rabbit synovial fibroblasts. Mol Cell Biochem 423:175–185. https://doi.org/10.1007/s11010-016-2835-6

    Article  PubMed  CAS  Google Scholar 

  35. Jiang C, Shao L, Wang Q, Dong Y (2012) Repetitive mechanical stretching modulates transforming growth factor-beta induced collagen synthesis and apoptosis in human patellar tendon fibroblasts. Biochem Cell Biol 90:667–674. https://doi.org/10.1139/o2012-024

    Article  PubMed  CAS  Google Scholar 

  36. Hawwa RL, Hokenson MA, Wang Y, Huang Z, Sharma S, Sanchez-Esteban J (2011) IL-10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch. Pediatr Pulmonol 46:640–649. https://doi.org/10.1002/ppul.21433

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, Madhur MS, Chen W, Harrison DG (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res 114:616–625. https://doi.org/10.1161/CIRCRESAHA.114.302157

    Article  PubMed  CAS  Google Scholar 

  38. Tian Y, Gawlak G, O’Donnell JJ, 3rd, Mambetsariev I, Birukova AA (2016) Modulation of endothelial inflammation by low and high magnitude cyclic stretch. PLoS ONE 11:e0153387. https://doi.org/10.1371/journal.pone.0153387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Turner NA (2011) Therapeutic regulation of cardiac fibroblast function: targeting stress-activated protein kinase pathways. Future Cardiol 7:673–691. https://doi.org/10.2217/fca.11.41

    Article  PubMed  CAS  Google Scholar 

  40. Wang J, Liu L, Xia Y, Wu D (2014) Silencing of poly(ADP-ribose) polymerase-1 suppresses hyperstretch-induced expression of inflammatory cytokines in vitro. Acta Biochim Biophys Sin 46:556–564. https://doi.org/10.1093/abbs/gmu035

    Article  PubMed  CAS  Google Scholar 

  41. Chian CF, Chiang CH, Chuang CH, Liu SL, Tsai CL (2016) SN50, a cell-permeable inhibitor of nuclear factor-kappaB, attenuates ventilator-induced lung injury in an isolated and perfused Rat Lung Model. Shock 46:194–201. https://doi.org/10.1097/SHK.0000000000000563

    Article  PubMed  CAS  Google Scholar 

  42. Sakkas LI, Chikanza IC, Platsoucas CD (2006) Mechanisms of disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol 2:679–685. https://doi.org/10.1038/ncprheum0346

    Article  PubMed  CAS  Google Scholar 

  43. Weidenbusch M, Anders HJ (2012) Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J Innate Immun 4:463–477. https://doi.org/10.1159/000336717

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81470431, 81773750, 81400214). We thank Silin Lv and Yufang Hou for the excellent technical support in Western blotting experiments, and Zheng Yan and Hongxu Wang for the help with data analysis. The authors thank members of Dr. Yang laboratory for discussions and suggestions.

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    Authors and Affiliations

    1. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China

      Wenqiang Gan, Tiegang Li, Chenghe Li, Ziliang Liu & Min Yang

    2. Department of Hypertension, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

      Jingyuan Ren

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    1. Wenqiang Gan
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    Contributions

    WG, TL, and MY participated in the design and execution of the study and wrote the manuscript. WG, TL, and JR performed most of the experiments. CL and ZL provided technical support. MY revised the manuscript. All authors read and approved the final manuscript.

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    Correspondence to Min Yang.

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    The authors declare no conflicts of interest.

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    Animals used in these experiments were handled in accordance with the Animal Management Rule of the Ministry of Health, People’s Republic of China (Documentation no. 55, 2001) and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996), approved by Animal Care and Use Committee.

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    Wenqiang Gan and Tiegang Li have contributed equally to this work.

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    Gan, W., Li, T., Ren, J. et al. Serum–glucocorticoid-regulated kinase 1 contributes to mechanical stretch-induced inflammatory responses in cardiac fibroblasts. Mol Cell Biochem 445, 67–78 (2018). https://doi.org/10.1007/s11010-017-3252-1

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