Advertisement

Molecular Medicine

, Volume 17, Issue 11–12, pp 1196–1203 | Cite as

Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression

  • Jennifer E. Bond
  • Andrew Bergeron
  • Peter Thurlow
  • M. Angelica Selim
  • Edith V. Bowers
  • Anna Kuang
  • Howard Levinson
Research Article

Abstract

Aberrant fibroblast migration in response to fibrogenic peptides plays a significant role in keloid pathogenesis. Angiotensin II (Ang II) is an octapeptide hormone recently implicated as a mediator of organ fibrosis and cutaneous repair. Ang II promotes cell migration but its role in keloid fibroblast phenotypic behavior has not been studied. We investigated Ang II signaling in keloid fibroblast behavior as a potential mechanism of disease. Primary human keloid fibroblasts were stimulated to migrate in the presence of Ang II and Ang II receptor 1 (AT1), Ang II receptor 2 (AT2) or nonmuscle myosin II (NMM II) antagonists. Keloid and the surrounding normal dermis were immunostained for NMM IIA, NMM IIB, AT2 and AT1, expression. Primary human keloid fibroblasts were stimulated to migrate with Ang II and the increased migration was inhibited by the AT1, antagonist EMD66684, but not the AT2 antagonist PD123319. Inhibition of the promigratory motor protein NMM II by addition of the specific NMM II antagonist blebbistatin inhibited Ang II-stimulated migration. Ang II stimulation of NMM II protein expression was prevented by AT1 blockade but not by AT2 antagonists. Immunostaining demonstrated increased NMM IIA, NMM IIB and AT1 expression in keloid fibroblasts compared with scant staining in normal surrounding dermis. AT2 immunostaining was absent in keloid and normal human dermal fibroblasts. These results indicate that Ang II mediates keloid fibroblast migration and possibly pathogenesis through AT1, activation and upregulation of NMM II.

Notes

Acknowledgments

The project was supported by an NIH Mentored Clinical Scientist Award (K08) grant GM085562-01 (to H. Levinson), a Plastic Surgery Education Foundation Fellowship and supplemental support from the Division of Plastic and Reconstructive Surgery and Departments of Pathology and Surgery at Duke University. The authors wish to thank Trung Ho for his help with immunohistology.

References

  1. 1.
    Butler PD, Longaker MT, Yang GP. (2008) Current progress in keloid research and treatment. J. Am. Coll. Surg. 206:731–41.CrossRefGoogle Scholar
  2. 2.
    Lee JY, Yang CC, Chao SC, Wong TW. (2004) Histopathological differential diagnosis of keloid and hypertrophic scar. Am. J. Dermatopathol. 26:379–84.CrossRefGoogle Scholar
  3. 3.
    Tuan TL, Nichter LS. (1998) The molecular basis of keloid and hypertrophic scar formation. Mol. Med. Today. 4:19–24.CrossRefGoogle Scholar
  4. 4.
    Atiyeh BS, Costagliola M, Hayek SN. (2005) Keloid or hypertrophic scar: the controversy: review of the literature. Ann. Plast. Surg. 54:676–80.CrossRefGoogle Scholar
  5. 5.
    Witt E, Maliri A, McGrouther DA, Bayat A. (2008) RAC activity in keloid disease: comparative analysis of fibroblasts from margin of keloid to its surrounding normal skin. Eplasty. 8:e19.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lim CP, Phan TT, Lim IJ, Cao X. (2006) Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration. Oncogene. 25:5416–25.CrossRefGoogle Scholar
  7. 7.
    Haisa M, Okochi H, Grotendorst GR. (1994) Elevated levels of PDGF alpha receptors in keloid fibroblasts contribute to an enhanced response to PDGF. J. Invest. Dermatol. 103:560–3.CrossRefGoogle Scholar
  8. 8.
    Yoshimoto H, et al. (1999) Overexpression of insulin-like growth factor-1 (IGF-I) receptor and the invasiveness of cultured keloid fibroblasts. Am. J. Pathol. 154:883–9.CrossRefGoogle Scholar
  9. 9.
    Fujiwara M, Muragaki Y, Ooshima A. (2005) Keloid-derived fibroblasts show increased secretion of factors involved in collagen turnover and depend on matrix metalloproteinase for migration. Br. J. Dermatol. 153:295–300.CrossRefGoogle Scholar
  10. 10.
    Murray JC. (1994) Keloids and hypertrophic scars. Clin. Dermatol. 12:27–37.CrossRefGoogle Scholar
  11. 11.
    Dzau VJ. (1988) Circulating versus local reninangiotensin system in cardiovascular homeostasis. Circulation. 77:14–13.CrossRefGoogle Scholar
  12. 12.
    de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol. Rev. 52:415–72.PubMedGoogle Scholar
  13. 13.
    Kim S, Iwao H. (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol. Rev. 52:11–34.PubMedGoogle Scholar
  14. 14.
    Steckelings UM, et al. (2004) Human skin: source of and target organ for angiotensin II. Exp. Dermatol. 13:148–54.CrossRefGoogle Scholar
  15. 15.
    Steckelings UM, Henz BM, Wiehstutz S, Unger T, Artuc M. (2005) Differential expression of angiotensin receptors in human cutaneous wound healing. Br. J. Dermatol. 153:887–93.CrossRefGoogle Scholar
  16. 16.
    Morihara K, et al. (2006) Cutaneous tissue angiotensin-converting enzyme may participate in pathologic scar formation in human skin. J. Am. Acad. Dermatol. 54:251–7.CrossRefGoogle Scholar
  17. 17.
    Audoly LP, Oliverio MI, Coffman TM. (2000) Insights into the functions of type 1 (AT1) angiotensin II receptors provided by gene targeting. Trends Endocrinol. Metab. 11:263–9.CrossRefGoogle Scholar
  18. 18.
    Kaschina E, Unger T. (2003) Angiotensin AT1/AT2 receptors: regulation, signalling and function. Blood Press. 12:70–88.CrossRefGoogle Scholar
  19. 19.
    Nickenig G, Geisen G, Vetter H, Sachinidis A. (1997) Characterization of angiotensin receptors on human skin fibroblasts. J. Mol. Med. 75:217–22.CrossRefGoogle Scholar
  20. 20.
    Kawaguchi Y, Kamatani N. (2002) Contribution of angiotensin II type I and type II receptors(AT-1 and AT-2) to collagen synthesis by skin fibroblasts [in Japanese]. Nippon Rinsho. 60:1940–1.PubMedGoogle Scholar
  21. 21.
    Kawaguchi Y, et al. (2004) Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Arthritis Rheum. 50:216–26.CrossRefGoogle Scholar
  22. 22.
    Yahata Y, et al. (2006) A novel function of angiotensin II in skin wound healing. Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated EGF receptor transactivation. J. Biol. Chem. 281:13209–16.CrossRefGoogle Scholar
  23. 23.
    Rodgers KE, et al. (2005) Fragments of Nle-angiotensin(1–7) accelerate healing in dermal models. J. Pept. Res. 66 Suppl 1:41–47.Google Scholar
  24. 24.
    Rodgers KE, et al. (2003) Acceleration of healing, reduction of fibrotic scar, and normalization of tissue architecture by an angiotensin analogue, NorLeu3-A(1–7). Plast. Reconstr. Surg. 111:1195–206.CrossRefGoogle Scholar
  25. 25.
    Cai Y, et al. (2006) Nonmuscle myosin IIA-dependent force inhibits cell spreading and drives F-actin flow. Biophys. J. 91:3907–20.CrossRefGoogle Scholar
  26. 26.
    Conti MA, Adelstein RS. (2008) Nonmuscle myosin II moves in new directions. J. Cell Sci. 121:11–8.CrossRefGoogle Scholar
  27. 27.
    Ridley AJ, et al. (2003) Cell migration: integrating signals from front to back. Science. 302:1704–1709.CrossRefGoogle Scholar
  28. 28.
    Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR. (2009) Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat. Rev. Mol. Cell. Biol. 10:778–90.CrossRefGoogle Scholar
  29. 29.
    Birnbaum S, et al. (2009) Further evidence for the involvement of MYH9 in the etiology of non-syndromic cleft lip with or without cleft palate. Eur. J. Oral Sci. 117:200–3.CrossRefGoogle Scholar
  30. 30.
    Even-Ram S, et al. (2007) Myosin IIA regulates cell motility and actomyosin-microtubule crosstalk. Nat. Cell. Biol 9:299–309.CrossRefGoogle Scholar
  31. 31.
    Kim S, Iwao H. (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol. Rev. 52:11–34.PubMedGoogle Scholar
  32. 32.
    Mederski WW, et al. (1994) Non-peptide angiotensin II receptor antagonists: synthesis and biological activity of a series of novel 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine derivatives. J. Med. Chem. 37:1632–45.CrossRefGoogle Scholar
  33. 33.
    Timmermans PB, et al. (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol. Rev. 45:205–51.PubMedGoogle Scholar
  34. 34.
    Matsubara H. (1998) Pathophysiological role of angiotensin II Type 2 receptor in cardiovascular and renal diseases. Circ. Res. 83:1182–91.CrossRefGoogle Scholar
  35. 35.
    Matsubara H, et al. (1994) Differential gene expression and regulation of angiotensin II receptor subtypes in rat cardiac fibroblasts and cardiomyocytes in culture. J. Clin. Invest. 93:1592–601.CrossRefGoogle Scholar
  36. 36.
    Villar-Cheda B, et al. (2010) Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson’s disease. Eur. J. Neurosci. 32:1695–706.CrossRefGoogle Scholar
  37. 37.
    Sasamura H, et al. (1997) Regulation of vascular type 1 angiotensin receptors by cytokines. Hypertension. 30:35–41.CrossRefGoogle Scholar
  38. 38.
    Rodgers K, et al. (2001) Development of angiotensin (1–7) as an agent to accelerate dermal repair. Wound Repair Regen. 9:238–47.CrossRefGoogle Scholar
  39. 39.
    Sun Y, Ramires FJ, Zhou G, Ganjam VK, Weber KT. (1997) Fibrous tissue and angiotensin II. J. Mol. Cell. Cardiol. 29:2001–12.CrossRefGoogle Scholar
  40. 40.
    Sun Y. (1997) Local angiotensin II and myocardial fibrosis. Adv. Exp. Med. Biol. 432:55–61.CrossRefGoogle Scholar
  41. 41.
    Van Liefde I, Vauquelin G. (2009) Sartan-AT1 receptor interactions: in vitro evidence for insurmountable antagonism and inverse agonism. Mol. Cell. Endocrinol. 302:237–43.CrossRefGoogle Scholar
  42. 42.
    Moen MD, Wagstaff AJ. (2005) Losartan: a review of its use in stroke risk reduction in patients with hypertension and left ventricular hypertrophy. Drugs. 65:2657–74.CrossRefGoogle Scholar
  43. 43.
    Birkenhager WH, de Leeuw PW. (1999) Non-peptide angiotensin type 1 receptor antagonists in the treatment of hypertension. J. Hypertens. 17:873–81.CrossRefGoogle Scholar
  44. 44.
    Atzori L, Pinna AL, Ferreli C, Aste N. (2006) Pityriasis rosea-like adverse reaction: review of the literature and experience of an Italian drug-surveillance center. Dermatol. Online. J. 12:1.PubMedGoogle Scholar
  45. 45.
    Femiano F. (2003) [Mucocutaneous bullous pemphigoid induced by valsartan. A clinical case]. Minerva Stomatol. 52:187–90.PubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Jennifer E. Bond
    • 1
  • Andrew Bergeron
    • 1
  • Peter Thurlow
    • 1
  • M. Angelica Selim
    • 2
  • Edith V. Bowers
    • 2
  • Anna Kuang
    • 3
  • Howard Levinson
    • 1
    • 2
  1. 1.Division of Plastic and Reconstructive Surgery, Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Department of PathologyDuke University Medical CenterDurhamUSA
  3. 3.Division of Plastic and Reconstructive Surgery, Department of SurgeryOregon Health and Science UniversityPortlandUSA

Personalised recommendations