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Titolo:
Fibroblast matrix gene expression and connective tissue remodeling: Role of endothelin-1
Autore:
Xu, SW; Denton, CP; Dashwood, MR; Holmes, AM; Bou-Gharios, G; Pearson, JD; Black, CM; Abraham, DJ;
Indirizzi:
Univ Coll London, Royal Free & Univ Coll Med Sch, Dept Med, Ctr Rheumatol,London NW3 2PF, England Univ Coll London London England NW3 2PF heumatol,London NW3 2PF, England Univ Coll London, Royal Free & Univ Coll Med Sch, Dept Mol Pathol, London NW3 2PF, England Univ Coll London London England NW3 2PF Pathol, London NW3 2PF, England Univ London Imperial Coll Sci Technol & Med, Sch Med, MRC, Ctr Clin Sci, London, England Univ London Imperial Coll Sci Technol & Med London England don, England Univ London Kings Coll, Sch Biomed Sci, Res Ctr Cardiovasc Biol & Med, London WC2R 2LS, England Univ London Kings Coll London England WC2R 2LS London WC2R 2LS, England
Titolo Testata:
JOURNAL OF INVESTIGATIVE DERMATOLOGY
fascicolo: 3, volume: 116, anno: 2001,
pagine: 417 - 425
SICI:
0022-202X(200103)116:3<417:FMGEAC>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
SCLERODERMA FIBROBLASTS; WOUND CONTRACTION; IN-VIVO; COLLAGEN; CELLS; LOCALIZATION; FIBROSIS; GROWTH; MYOFIBROBLASTS; RECEPTORS;
Keywords:
collagens; endothelin-1; endothelin receptors; extracellular matrix; fibroblasts; interstitial collagenase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: Abraham, DJ Univ Coll London, Royal Free & Univ Coll Med Sch, Dept Med, Ctr Rheumatol,Royal Free Campus,Rowland Hill St, London NW3 2PF, England UnivColl London Royal Free Campus,Rowland Hill St London England NW3 2PF
Citazione:
S.W. Xu et al., "Fibroblast matrix gene expression and connective tissue remodeling: Role of endothelin-1", J INVES DER, 116(3), 2001, pp. 417-425

Abstract

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosisfibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 07:08:21