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Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis. Am J Physiol Cell Physiol 2011 Mar;300(3):C550-6

Date

12/17/2010

Pubmed ID

21160034

Pubmed Central ID

PMC3063974

DOI

10.1152/ajpcell.00123.2010

Scopus ID

2-s2.0-79952158516   26 Citations

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.

Author List

Xu H, Zaidi M, Struve J, Jones DW, Krolikowski JG, Nandedkar S, Lohr NL, Gadicherla A, Pagel PS, Csuka ME, Pritchard KA, Weihrauch D

Authors

Mary Ellen Csuka MD Professor in the Medicine department at Medical College of Wisconsin
Nicole L. Lohr MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Proliferation
Cells, Cultured
Chronic Disease
Disease Models, Animal
Endothelial Cells
Female
Fibrillin-1
Fibrillins
Humans
Male
Mesoderm
Mice
Mice, Inbred C57BL
Microfilament Proteins
Molecular Weight
Neovascularization, Physiologic
Oxidative Stress
Scleroderma, Systemic
jenkins-FCD Prod-410 e9586552fe7f53c71f7923aa6e27aeabbd3c2473