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CC BY-NC 4.0 · Arch Plast Surg 2015; 42(01): 11-19
DOI: 10.5999/aps.2015.42.1.11
Original Article

KCl Mediates K+ Channel-Activated Mitogen-Activated Protein Kinases Signaling in Wound Healing

Jung Hee Shim
Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
,
Jong Woo Lim
Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
,
Byeong Kyu Kim
Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
,
Soo Jin Park
Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
,
Suk Wha Kim
Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
,
Tae Hyun Choi
Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
› Author AffiliationsThis study was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2010-0022472) and the Seoul National University Brain Fusion Program Research Grant.
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Background Wound healing is an interaction of a complex signaling cascade of cellular events, including inflammation, proliferation, and maturation. K+ channels modulate the mitogen-activated protein kinase (MAPK) signaling pathway. Here, we investigated whether K+ channel-activated MAPK signaling directs collagen synthesis and angiogenesis in wound healing.

Methods The human skin fibroblast HS27 cell line was used to examine cell viability and collagen synthesis after potassium chloride (KCl) treatment by Cell Counting Kit-8 (CCK-8) and western blotting. To investigate whether K+ ion channels function upstream of MAPK signaling, thus affecting collagen synthesis and angiogenesis, we examined alteration of MAPK expression after treatment with KCl (channel inhibitor), NS1619 (channel activator), or kinase inhibitors. To research the effect of KCl on angiogenesis, angiogenesis-related proteins such as thrombospondin 1 (TSP1), anti-angiogenic factor, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), pro-angiogenic factor were assayed by western blot.

Results The viability of HS27 cells was not affected by 25 mM KCl. Collagen synthesis increased dependent on time and concentration of KCl exposure. The phosphorylations of MAPK proteins such as extracellular-signal-regulated kinase (ERK) and p38 increased about 2.5-3 fold in the KCl treatment cells and were inhibited by treatment of NS1619. TSP1 expression increased by 100%, bFGF expression decreased by 40%, and there is no significant differences in the VEGF level by KCl treatment, TSP1 was inhibited by NS1619 or kinase inhibitors.

Conclusions Our results suggest that KCl may function as a therapeutic agent for wound healing in the skin through MAPK signaling mediated by the K+ ion channel.

Keywords

Potassium channels - Mitogen activated protein kinases - Wound healing - Angiogenesis


Publication History

Received: 27 June 2014

Accepted: 29 October 2014

Article published online:
05 May 2022

© 2015. The Korean Society of Plastic and Reconstructive Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonCommercial License, permitting unrestricted noncommercial use, distribution, and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes. (https://creativecommons.org/licenses/by-nc/4.0/)

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  • References

  • 1 Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003; 83: 835-870
    CrossrefPubMedSearch in Google Scholar
  • 2 Sinno H, Prakash S. Complements and the wound healing cascade: an updated review. Plast Surg Int 2013; 2013: 146764
    PubMedSearch in Google Scholar
  • 3 Oryan A. Role of collagen in soft connective tissue wound healing. Transplant Proc 1995; 27: 2759-2761
    PubMedSearch in Google Scholar
  • 4 Bellamy G, Bornstein P. Evidence for procollagen, a biosynthetic precursors of collagen. Proc Natl Acad Sci U S A 1971; 68: 1138-1142
    CrossrefPubMedSearch in Google Scholar
  • 5 Kivirikko KI, Risteli L. Biosynthesis of collagen and its alterations in pathological states. Med Biol 1976; 54: 159-186
    Search in Google Scholar
  • 6 Petrov VV, Fagard RH, Lijnen PJ. Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension 2002; 39: 258-263
    CrossrefPubMedSearch in Google Scholar
  • 7 Kothapalli D, Frazier KS, Welply A. et al. Transforming growth factor beta induces anchorage-independent growth of NRK fibroblasts via a connective tissue growth factor-dependent signaling pathway. Cell Growth Differ 1997; 8: 61-68
    PubMedSearch in Google Scholar
  • 8 Kothapalli D, Hayashi N, Grotendorst GR. Inhibition of TGF-beta-stimulated CTGF gene expression and anchorage-independent growth by cAMP identifies a CTGF-dependent restriction point in the cell cycle. FASEB J 1998; 12: 1151-1161
    CrossrefPubMedSearch in Google Scholar
  • 9 Duncan MR, Frazier KS, Abramson S. et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J 1999; 13: 1774-1786
    CrossrefPubMedSearch in Google Scholar
  • 10 Derynck R, Feng XH. TGF-beta receptor signaling. Biochim Biophys Acta 1997; 1333: F105-F150
    PubMedSearch in Google Scholar
  • 11 Roberts AB, Derynck R. Meeting report: signaling schemes for TGF-beta. Sci STKE 2001; 2001: pe43
    PubMedSearch in Google Scholar
  • 12 Na JI, Choi JW, Choi HR. et al. Rapid healing and reduced erythema after ablative fractional carbon dioxide laser resurfacing combined with the application of autologous platelet-rich plasma. Dermatol Surg 2011; 37: 463-468
    CrossrefPubMedSearch in Google Scholar
  • 13 Tan K, Duquette M, Liu JH. et al. Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implication. J Cell Biol 2002; 159: 373-382
    CrossrefPubMedSearch in Google Scholar
  • 14 Blake SM, Strasser V, Andrade N. et al. Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration. EMBO J 2008; 27: 3069-3080
    CrossrefPubMedSearch in Google Scholar
  • 15 Andrikopoulos P, Fraser SP, Patterson L. et al. Angiogenic functions of voltage-gated Na+ Channels in human endothelial cells: modulation of vascular endothelial growth factor (VEGF) signaling. J Biol Chem 2011; 286: 16846-16860
    CrossrefPubMedSearch in Google Scholar
  • 16 Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium. Physiol Rev 2001; 81: 1415-1459
    CrossrefPubMedSearch in Google Scholar
  • 17 Robson MC. The role of growth factors in the healing of chronic wounds. Wound Repair Regen 1997; 5: 12-17
    CrossrefPubMedSearch in Google Scholar
  • 18 Witte MB, Barbul A. General principles of wound healing. Surg Clin North Am 1997; 77: 509-528
    CrossrefPubMedSearch in Google Scholar
  • 19 Boateng JS, Matthews KH, Stevens HN. et al. Wound healing dressings and drug delivery systems: a review. J Pharm Sci 2008; 97: 2892-2923
    CrossrefPubMedSearch in Google Scholar
  • 20 Barrientos S, Brem H, Stojadinovic O. et al. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen 2014; 22: 569-578
    CrossrefPubMedSearch in Google Scholar
  • 21 Pakyari M, Farrokhi A, Maharlooei MK. et al. Critical role of transforming growth factor beta in different phases of wound healing. Adv Wound Care (New Rochelle) 2013; 2: 215-224
    CrossrefPubMedSearch in Google Scholar
  • 22 Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003; 425: 577-584
    Search in Google Scholar
  • 23 Yuan LL, Adams JP, Swank M. et al. Protein kinase modulation of dendritic K+ channels in hippocampus involves a mitogen-activated protein kinase pathway. J Neurosci 2002; 22: 4860-4868
    CrossrefPubMedSearch in Google Scholar
  • 24 Trinh NT, Prive A, Kheir L. et al. Involvement of KATP and KvLQT1 K+ channels in EGF-stimulated alveolar epithelial cell repair processes. Am J Physiol Lung Cell Mol Physiol 2007; 293: L870-L882
    CrossrefPubMedSearch in Google Scholar
  • 25 Veliceasa D, Ivanovic M, Hoepfner FT. et al. Transient potential receptor channel 4 controls thrombospondin-1 secretion and angiogenesis in renal cell carcinoma. FEBS J 2007; 274: 6365-6377
    Search in Google Scholar