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The role of KCa3.1 channels in cardiac fibrosis induced by pressure overload in rats

  • Ion channels, receptors and transporters
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The intermediate-conductance Ca2+-activated K+ (KCa3.1) channels play a pivotal role in the proliferation and collagen secretion of cardiac fibroblasts. However, their contribution in cardiac fibrosis remains unknown. This study was designed to investigate whether KCa3.1 channels mediate the development of cardiac fibrosis. Pressure-overloaded rats were induced by abdominal aortic constriction and treated without or with KCa3.1 blocker (TRAM-34) or angiotensin type 1 receptor blocker (losartan) for 2 weeks. Besides the increase of blood pressure, angiotensin (Ang) II level in the plasma and myocardium, left ventricle mass and hydroxyproline concentration, myocardial hypertrophy, as well as significant collagen deposition in the perivascular regions and interstitium of the myocardium were observed in pressure-overloaded rats. The expression of leukocyte differentiation antigens (CD45 and CD3), macrophage surface marker (F4/80), tumor necrosis factor alpha, and monocyte chemotactic protein-1 (MCP-1) also significantly increased. All these alterations were prevented by losartan and TRAM-34. TRAM-34 also reduced the increase of renin and angiotensinogen in the plasma and myocardium of pressure-overloaded rats. Ang II promoted the migration of monocytes through endothelial cells and the secretion of MCP-1 from human umbilical vein endothelial cells in vitro, which was inhibited by TRAM-34. In conclusion, the present study demonstrates that TRAM-34 alleviates cardiac fibrosis induced by pressure overload, which is related to its inhibitory action on KCa3.1 channels and Ang II level. Our findings indicate that the inhibition of KCa3.1 channels may represent a novel approach of preventing the progression of cardiac fibrosis, and also add to the already developing literature of promising targets for TRAM-34.

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References

  1. Aiello VD, Reis MM, Benvenuti LA, Higuchi Mde L, Ramires JA, Halperin JA (2002) A possible role for complement in the pathogenesis of chronic chagasic cardiomyopathy. J Pathol 197(2):224–229

    Article  CAS  PubMed  Google Scholar 

  2. Banerjee I, Yekkala K, Borg TK, Baudino TA (2006) Dynamic interactions between myocytes, fibroblasts, and extracellular matrix. Ann N Y Acad Sci 1080:76–84

    Article  CAS  PubMed  Google Scholar 

  3. Camelliti P, Borg TK, Kohl P (2005) Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 65:40–51

    Article  CAS  PubMed  Google Scholar 

  4. Chung I, Zelivyanskaya M, Gendelman HE (2002) Mononuclear phagocyte biophysiology influences brain transendothelial and tissue migration: implication for HIV-1-associated dementia. J Neuroimmunol 122:40–54

    Article  CAS  PubMed  Google Scholar 

  5. Cittadini A, Isgaard J, Monti MG, Casaburi C, Di Gianni A, Serpico R, Iaccarino G, Saccà L (2003) Growth hormone prolongs survival in experimental postinfarction heart failure. J Am Coll Cardiol 41:2154–2163

    Article  CAS  PubMed  Google Scholar 

  6. Cruse G, Duffy SM, Brightling CE, Bradding P (2006) Functional KCa3.1 K+ channels are required for human lung mast cell migration. Thorax 61:880–885

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Deng XL, Lau CP, Lai K, Cheung KF, Lau GK, Li GR (2007) Cell cycle-dependent expression of potassium channels and cell proliferation in rat mesenchymal stem cells from bone marrow. Cell Prolif 40:656–670

    Article  CAS  PubMed  Google Scholar 

  8. Di L, Srivastava S, Zhdanova O, Sun Y, Li Z, Skolnik EY (2010) Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation. J Biol Chem 285:38765–38771

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Duerrschmid C, Crawford JR, Reineke E, Taffet GE, Trial J, Entman ML, Haudek SB (2013) TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis. J Mol Cell Cardiol 57:59–67

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Frangogiannis NG, Dewald O, Xia Y, Ren G, Haudek S, Leucker T, Kraemer D, Taffet G, Rollins BJ, Entman ML (2007) Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. Circulation 115:584–592

    Article  CAS  PubMed  Google Scholar 

  11. Frangogiannis NG, Entman ML (2005) Chemokines in myocardial ischemia. Trends Cardiovasc Med 15:163–169

    Article  CAS  PubMed  Google Scholar 

  12. Ghanshani S, Wulff H, Miller MJ, Rohm H, Neben A, Gutman GA, Cahalan MD, Chandy KG (2000) Up-regulation of the IKCa1 potassium channel during T-cell activation: molecular mechanism and functional consequences. J Biol Chem 275:37137–37149

    Article  CAS  PubMed  Google Scholar 

  13. Gonzalez A, Lopez B, Querejeta R, Diez J (2002) Regulation of myocardial fibrillar collagen by angiotensin II. A role in hypertensive heart disease? J Mol Cell Cardiol 34:1585–1593

    Article  CAS  PubMed  Google Scholar 

  14. Grgic I, Kiss E, Kaistha BP, Busch C, Kloss M, Sautter J, Müller A, Kaistha A, Schmidt C, Raman G, Wulff H, Strutz F, Gröne HJ, Köhler R, Hoyer J (2009) Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proc Natl Acad Sci U S A 106:14518–14523

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Han YL, Li YL, Jia LX, Cheng JZ, Qi YF, Zhang HJ, Du J (2012) Reciprocal interaction between macrophages and T cells stimulates IFN-γ and MCP-1 production in Ang II-induced cardiac inflammation and fibrosis. PLoS One 7:e35506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Haudek SB, Cheng J, Du J, Wang Y, Hermosillo-Rodriguez J, Trial J, Taffet GE, Entman ML (2010) Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy. J Mol Cell Cardiol 49:499–507

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Haudek SB, Taffet GE, Schneider MD, Mann DL (2007) TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest 117:2692–2701

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Haudek SB, Xia Y, Huebener P, Lee JM, Carlson S, Crawford JR, Pilling D, Gomer RH, Trial J, Frangogiannis NG, Entman ML (2006) Bone marrow derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci U S A 103:18284–18289

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Huang C, Shen S, Ma Q, Chen J, Gill A, Pollock CA, Chen XM (2013) Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice. Diabetes 62:2923–2934

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Jager H, Dreker T, Buck A, Giehl K, Gress T, Grissmer S (2004) Blockage of intermediate-conductance Ca2+-activated K+ channels inhibit human pancreatic cancer cell growth in vitro. Mol Pharmacol 65:630–638

    Article  PubMed  Google Scholar 

  21. Katoh M, Kurosawa Y, Tanaka K, Watanabe A, Doi H, Narita H (2001) Fluvastatin inhibits O2 and ICAM-1 levels in a rat model with aortic remodeling induced by pressure overload. Am J Physiol Heart Circ Physiol 281:H655–H660

    CAS  PubMed  Google Scholar 

  22. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123:594–604

    Article  CAS  PubMed  Google Scholar 

  23. Kuras Z, Yun YH, Chimote AA, Neumeier L, Conforti L (2012) KCa3.1 and TRPM7 channels at the uropod regulate migration of activated human T cells. PLoS One 7:e43859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Ma FF, Li YL, Jia LX, Han YL, Cheng JZ, Li HH, Qi YF, Du J (2012) Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS One 7:e35144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Mann DL (2002) Angiotensin II as an inflammatory mediator: evolving concepts in the role of the renin angiotensin system in the failing heart. Cardiovasc Drugs Ther 16:7–9

    Article  CAS  PubMed  Google Scholar 

  26. Mene P, Pirozzi N (2010) Potassium channels: the ‘master switch’ of renal fibrosis? Nephrol Dial Transplant 25:353–355

    Article  CAS  PubMed  Google Scholar 

  27. Parihar AS, Coghlan MJ, Gopalakrishnan M, Shieh CC (2003) Effects of intermediate-conductance Ca2+-activated K+ channel modulators on human prostate cancer cell proliferation. Eur J Pharmacol 471:157–164

    Article  CAS  PubMed  Google Scholar 

  28. Qi G, Jia L, Li Y, Bian Y, Cheng J, Li H, Xiao C, Du J (2011) Angiotensin II infusion-induced inflammation, monocytic fibroblast precursor infiltration, and cardiac fibrosis are pressure dependent. Cardiovasc Toxicol 11:157–167

    Article  CAS  PubMed  Google Scholar 

  29. Ren J, Yang M, Qi G, Zheng J, Jia L, Cheng J, Tian C, Li H, Lin X, Du J (2011) Proinflammatory protein CARD9 is essential for infiltration of monocytic fibroblast precursors and cardiac fibrosis caused by angiotensin II infusion. Am J Hypertens 24:701–707

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Saito T, Fujiwara Y, Fujiwara R, Hasegawa H, Kibira S, Miura H, Miura M (2002) Role of augmented expression of intermediate-conductance Ca2+-activated K+ channels in postischaemic heart. Clin Exp Pharmacol Physiol 29:324–329

    Article  CAS  PubMed  Google Scholar 

  31. Sandra BH, JoAnn T, Ying X, Damon G, Darrell P, Mark LE (2008) Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells. PNAS 105:10179–10184

    Article  Google Scholar 

  32. Schilling T, Eder C (2007) TRAM-34 inhibits nonselective cation channels. Pflugers Arch 454:559–563

    Article  CAS  PubMed  Google Scholar 

  33. Schilling T, Stock C, Schwab A, Eder C (2004) Functional importance of Ca2+-activated K+ channels for lysophosphatidic acid-induced microglia migration. Eur J Neurosci 19:1469–1474

    Article  PubMed  Google Scholar 

  34. Sekiguchi K, Li X, Coker M, Flesch M, Barger PM, Sivasubramanian N, Mann DL (2004) Cross regulation between the renin–angiotensin system and inflammatory mediators in cardiac hypertrophy and failure. Cardiovasc Res 63:433–442

    Article  CAS  PubMed  Google Scholar 

  35. Su XL, Wang Y, Zhang W, Li GR, Deng XL (2011) Insulin-mediated upregulation of KCa3.1 channels promotes cell migration and proliferation in rat vascular smooth muscle. J Mol Cell Cardiol 51:51–57

    Article  CAS  PubMed  Google Scholar 

  36. Tao R, Lau CP, Tse HF, Li GR (2008) Regulation of cell proliferation by intermediate-conductance Ca2+-activated potassium and volume-sensitive chloride channels in mouse mesenchymal stem cells. Am J Physiol Cell Physiol 295:C1409–C1416

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Tharp DL, Wamhoff BR, Turk JR, Bowles DK (2006) Upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle. Am J Physiol Heart Circ Physiol 291:H2493–H2503

    Article  CAS  PubMed  Google Scholar 

  38. Wang LP, Wang Y, Zhao LM, Li GR, Deng XL (2013) Angiotensin II upregulates KCa3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts. Biochem Pharmacol 85:1486–1494

    Article  CAS  PubMed  Google Scholar 

  39. Wulff H, Miller MJ, Hansel W, Grissmer S, Cahalan MD, Chandy KG (2000) Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci U S A 97:8151–8156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. 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

    Article  CAS  PubMed  Google Scholar 

  41. Yu ZH, Xu JR, Wang YX, Xu GN, Xu ZP, Yang K, Wu DZ, Cui YY, Chen HZ (2013) Targeted inhibition of KCa3.1 channel attenuates airway inflammation and remodeling in allergic asthma. Am J Respir Cell Mol Biol 48:685–693

    Article  CAS  PubMed  Google Scholar 

  42. Zhao LM, Su XL, Wang Y, Li GR, Deng XL (2013) KCa3.1 channels mediate the increase of cell migration and proliferation by advanced glycation endproducts in cultured rat vascular smooth muscle cells. Lab Invest 93:159–167

    Article  CAS  PubMed  Google Scholar 

  43. Zhao LM, Zhang W, Wang LP, Li GR, Deng XL (2012) Advanced glycation end products promote proliferation of cardiac fibroblasts by upregulation of KCa3.1 channels. Pflug Arch 464:613–621

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Nature Science Foundation of China (grant numbers 81170137 and 81370191).

Ethical standards

Experimental protocols were approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University and conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, USA.

Disclosures

None was declared.

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    Authors and Affiliations

    1. Department of Physiology and Pathophysiology, School of Medicine, Xi’an Jiaotong University, 76 West Yanta Road, Xi’an, 710061, Shaanxi, China

      Li-Mei Zhao, Li-Ping Wang, Xiao-Zhen Ma & Xiu-Ling Deng

    2. Cardiovascular Research Center, School of Medicine, Xi’an Jiaotong University, 76 West Yanta Road, Xi’an, 710061, Shaanxi, China

      Li-Mei Zhao & Xiu-Ling Deng

    3. Department of Physiology, School of Basic Medical Science, Hebei United University, 57 Jianshe South Road, Tangshan, 063000, Hebei, China

      Li-Ping Wang

    4. Department of Pathology, Xi’an Guangren Hospital, Affiliated to School of Medicine, Xi’an Jiaotong University, 76 West Yanta Road, Xi’an, 710004, Shaanxi, China

      Hui-Fang Wang

    5. Department of Pathology, School of Medicine, Xi’an Jiaotong University, 76 West Yanta Road, Xi’an, 710061, Shaanxi, China

      Dang-Xia Zhou

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    1. Li-Mei Zhao
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    Correspondence to Xiu-Ling Deng.

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    Li-Mei Zhao and Li-Ping Wang contributed equally to this work.

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    Zhao, LM., Wang, LP., Wang, HF. et al. The role of KCa3.1 channels in cardiac fibrosis induced by pressure overload in rats. Pflugers Arch - Eur J Physiol 467, 2275–2285 (2015). https://doi.org/10.1007/s00424-015-1694-4

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