title: Angiotensin-II mediates nonmuscle myosin II activation and expression and contributes to human keloid disease progression.
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.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Bond
authors.forename: Andrew
authors.initials: A
authors.lastname: Bergeron
authors.forename: Peter
authors.initials: P
authors.lastname: Thurlow
authors.forename: M Angelica
authors.initials: MA
authors.lastname: Selim
authors.forename: Edith V
authors.initials: EV
authors.lastname: Bowers
authors.forename: Anna
authors.initials: A
authors.lastname: Kuang
authors.forename: Howard
authors.initials: H
authors.lastname: Levinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020405:Dermis / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007627:Keloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins / Q000235:genetics / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D024501:Nonmuscle Myosin Type IIB / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D055815:Young Adult
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D020033:Protein Isoforms; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains