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
12/17/2010Pubmed ID
21160034Pubmed Central ID
PMC3063974DOI
10.1152/ajpcell.00123.2010Scopus ID
2-s2.0-79952158516 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
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 DAuthors
Mary Ellen Csuka MD Professor in the Medicine department at Medical College of WisconsinKirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCell 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
