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Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo.

Title: Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo.
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Name(s): Challa, Azariyas A, author
Vukmirovic, Milica, author
Blackmon, John, author
Stefanovic, Branko, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2012-01-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Type I collagen is the most abundant protein in the human body. Its excessive synthesis results in fibrosis of various organs. Fibrosis is a major medical problem without an existing cure. Excessive synthesis of type I collagen in fibrosis is primarily due to stabilization of collagen mRNAs. We recently reported that intermediate filaments composed of vimentin regulate collagen synthesis by stabilizing collagen mRNAs. Vimentin is a primary target of Withaferin-A (WF-A). Therefore, we hypothesized that WF-A may reduce type I collagen production by disrupting vimentin filaments and decreasing the stability of collagen mRNAs. This study is to determine if WF-A exhibits anti-fibrotic properties in vitro and in vivo and to elucidate the molecular mechanisms of its action. In lung, skin and heart fibroblasts WF-A disrupted vimentin filaments at concentrations of 0.5-1.5 µM and reduced 3 fold the half-lives of collagen α1(I) and α2(I) mRNAs and protein expression. In addition, WF-A inhibited TGF-β1 induced phosphorylation of TGF-β1 receptor I, Smad3 phosphorylation and transcription of collagen genes. WF-A also inhibited in vitro activation of primary hepatic stellate cells and decreased their type I collagen expression. In mice, administration of 4 mg/kg WF-A daily for 2 weeks reduced isoproterenol-induced myocardial fibrosis by 50%. Our findings provide strong evidence that Withaferin-A could act as an anti-fibrotic compound against fibroproliferative diseases, including, but not limited to, cardiac interstitial fibrosis.
Identifier: FSU_pmch_22900077 (IID), 10.1371/journal.pone.0042989 (DOI), PMC3416765 (PMCID), 22900077 (RID), 22900077 (EID), PONE-D-12-16085 (PII)
Grant Number: 5R01DK059466-08
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416765.
Subject(s): Animals
Cell Line
Collagen Type I/genetics
Collagen Type I/metabolism
Endomyocardial Fibrosis/chemically induced
Endomyocardial Fibrosis/drug therapy
Endomyocardial Fibrosis/genetics
Endomyocardial Fibrosis/pathology
Fibroblasts/drug effects
Fibroblasts/metabolism
Gene Expression Regulation/drug effects
Gene Knockout Techniques
Hepatic Stellate Cells/drug effects
Hepatic Stellate Cells/metabolism
Humans
Isoproterenol/adverse effects
Male
Mice
Phosphorylation/drug effects
Promoter Regions, Genetic
Proteolysis/drug effects
RNA Stability/drug effects
RNA, Messenger/genetics
RNA, Messenger/metabolism
Smad3 Protein/metabolism
Transforming Growth Factor beta1/pharmacology
Vimentin/genetics
Vimentin/metabolism
Withanolides/administration & dosage
Withanolides/pharmacology
Withanolides/toxicity
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_22900077
Owner Institution: FSU
Is Part Of: PloS one.
1932-6203
Issue: iss. 8, vol. 7

Choose the citation style.
Challa, A. A., Vukmirovic, M., Blackmon, J., & Stefanovic, B. (2012). Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo. Plos One. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_22900077