title: Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis.
abstract: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by oxidative stress, impaired vascular function, and attenuated angiogenesis. The tight-skin (Tsk(-/+)) mouse is a model of SSc that displays many of the cellular features of the clinical disease. We tested the hypotheses that abnormal fibrillin-1 expression and chronic phospholipid oxidation occur in Tsk(-/+) mice and, furthermore, that these factors precipitate a prooxidant state, collagen-related protein expression, apoptosis, and mesenchymal transition in endothelial cells cultured on Tsk(-/+) extracellular matrix. Human umbilical vein endothelial cells were seeded on microfibrils isolated from skin of C57BL/6J (control) and Tsk(-/+) mice in the presence or absence of chronic pretreatment with the apolipoprotein Apo A-I mimetic D-4F (1 mg·kg(-1)·day(-1) ip for 6 to 8 wk). Nitric oxide-to-superoxide anion ratio was assessed 12 h after culture, and cell proliferation, apoptosis, and phenotype were studied 72 h after culture. Tsk(-/+) mice demonstrated abnormal "big fibrillin" expression (405 kDa) by Western blot analysis compared with control. Endothelial cells cultured on microfibrils prepared from Tsk(-/+) mice demonstrated reduced proliferation, a prooxidant state (reduced nitric oxide-to-superoxide anion ratio), increased apoptosis, and collagen-related protein expression associated with mesenchymal transition. Chronic D-4F pretreatment of Tsk(-/+) mice attenuated many of these adverse effects. The findings demonstrate that abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in Tsk(-/+) mice. This mesenchymal transition may contribute to the reduction in angiogenesis that is known to occur in this model of SSc.
authors.affiliation: Dept. of Anesthesiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Maria
authors.initials: M
authors.lastname: Zaidi
authors.forename: Janine
authors.initials: J
authors.lastname: Struve
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.forename: John G
authors.initials: JG
authors.lastname: Krolikowski
authors.forename: Sandhya
authors.initials: S
authors.lastname: Nandedkar
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Lohr
authors.forename: Ashish
authors.initials: A
authors.lastname: Gadicherla
authors.forename: Paul S
authors.initials: PS
authors.lastname: Pagel
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Csuka
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
authors.forename: Dorothée
authors.initials: D
authors.lastname: Weihrauch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D008970:Molecular Weight; D018919:Neovascularization, Physiologic / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse