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Ac-SDKP inhibits transforming growth factor-[beta]1-induced differentiation of human cardiac fibroblasts into myofibroblasts
- Source :
- The American Journal of Physiology. May, 2010, Vol. 298 Issue 5, pH1357, 8 p.
- Publication Year :
- 2010
-
Abstract
- N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits collagen production and cell proliferation in cultured rat cardiac fibroblasts, but its effect on differentiation of fibroblasts into myofibroblasts is not known. High amounts of transforming growth factor-[beta]1 (TGF-[beta]1) have been found in fibrotic cardiac tissue. TGF-[beta]1 converts fibroblasts into myofibroblasts, which produce more extracellular matrix proteins than fibroblasts. We hypothesized that 1) Ac-SDKP inhibits TGF-[beta]1-induced differentiation of fibroblasts into myofibroblasts; and 2) this effect is mediated in part by blocking phosphorylation of small-mothers-against-decapentaplegic (Smad) 2 and extracellular signal-regulated kinase (ERK) 1/2. For this study, we used human fetal cardiac fibroblasts (HCFs), which do not spontaneously become myofibroblasts when cultured at low passages. We investigated the effect of Ac-SDKP on TGF-[beta]1-induced HCF transformation into myofibroblasts, Smad2 and ERK1/2 phosphorylation, Smad7 expression, cell proliferation, and collagen production. We also investigated TGF-[beta]1 production by HCFs stimulated with endothelin-1 (ET-1). As expected, HCFs treated with TGF-[beta]1 transformed into myofibroblasts as indicated by increased expression of [alpha]-smooth muscle actin and a higher proportion of the embryonic isoform of smooth muscle myosin compared with untreated cells. TGF-[beta]1 also increased Smad2 and ERK1/2 phosphorylation but did not affect Smad7 expression. In addition. TGF-[beta]1 stimulated HCF proliferation as indicated by an increase in mitochondrial dehydrogenase activity and collagen production (hydroxyproline assay). AcSDKP significantly inhibited all of the effects of TGF-[beta]1. It also inhibited ET-l-stimulated TGF-[beta]1 production. We concluded that Ac-SDKP markedly suppresses differentiation of human cardiac fibroblasts into myofibroblasts, probably by inhibiting the TGF-[beta]/ Smad/ERK1/2 signaling pathway, and thus mediating its anti-fibrotic effects. transforming growth factor-[beta]1; human cardiac myofibroblasts; N-acetyl-seryl-aspartyl-lysyl-proline; collagen; signal transduction; fibroblast differentiation doi: 10.1152/ajpheart.00464.2009.
Details
- Language :
- English
- ISSN :
- 00029513
- Volume :
- 298
- Issue :
- 5
- Database :
- Gale General OneFile
- Journal :
- The American Journal of Physiology
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.227181799