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Fibulin-2 regulates Angiotensin II-induced fibrotic response in cultured cardiac fibroblasts via modulating TGF-beta1 signaling
Zhao Yongxi,Wu Jing * #
School of Life Science and Technology, Xi'an Jiaotong University, Xi'an City, 710049
*Correspondence author
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Funding: none
Opened online:22 November 2013
Accepted by: none
Citation: Zhao Yongxi,Wu Jing.Fibulin-2 regulates Angiotensin II-induced fibrotic response in cultured cardiac fibroblasts via modulating TGF-beta1 signaling[OL]. [22 November 2013] http://en.paper.edu.cn/en_releasepaper/content/4564806
 
 
Fibulin-2, a typical product of fibroblasts, has been recently implicated in physiological or pathological ECM remodeling and tissue fibrosis, but the roles and underlying mechanisms remain obscure. Angiotensin II (Ang-II) and TGF-beta play a pivotal role in cardiac remodeling, which do not act independently from one another but rather act as part of a signalling network to promote cardiac remodeling. The cardiac fibroblasts (CFs), the most abundant cell type present in the heart, are responsible for the deposition of extracellular matrix. The present study was designed to investigate the role and molecular mechanisms of fibulin-2 in Ang-II-induced ECM changes and TGF-beta signaling pathway in cultured CFs. Methods: CFs were isolated from wild type (WT) and fibulin-2 deficient (Fbln2-/-) adult mice in C57BL/6 background, and treated with Ang-II, Ang-II plus neutralizing antibody to TGF-beta, or recombinant TGF-beta1 for 24h. Real-time RT-PCR was performed to assess mRNA expression of collagen type I (Col I), type III (Col III), fibulin-2 (FBLN2), TGF-beta1 and MMP-2. ELISA assay and gelatin zymographic analysis were performed to examine TGF-beta1 concentration and MMP-2 activity in the conditioned culture medium. Western blot analysis was performed to detect Smad-2 and p-Smad2 protein expression. Results: FBLN2 mRNA was markedly up-regulated in WT CFs by Ang-II, and partially decreased when plus neutralizing antibody to TGF-beta. In FBLN2-/- CFs, there was no FBLN2 mRNA detected. There was no discernible difference in mRNA expression of Col I, Col III, TGF-beta1 and MMP-2 between control WT and Fblin2-/- CFs. Ang-II treated WT CFs showed significant increase in Col I, Col III, TGF-beta1 and MMP-2 mRNA expression from control. Compared to WT CFs, Fbln2-/- CFs induced by Ang-II showed a significantly less extent increase in these markers. MMP-2 activity showed essentially identical patterns to relative MMP-2 mRNA levels. TGF-beta1 concentration in WT supernatants was significantly elevated by Ang-II but not in Fbln2-/- supernatants. Smad2 expression was not changed by Ang-II, however p-Smad2, was significantly increased by Ang-II in WT CFs but not in Fbln2-/- CFs. Plus neutralizing antibody to TGF-beta, up-regulation of Col I, Col III, TGF-beta1 and MMP-2 expression, MMP-2 activity, and Smad2 phosphorylation induced by Ang-II in WT CFs was partially reduced, but no significant effects on FBLN2-/- CFs. Conclusion: Fibulin-2 enhanced Ang-II-induced ECM remodeling (increased collagen synthesis and MMP activation), which was partially mediated by TGF-beta activation. TGF-beta mediated positive feedback loop plays a central role in Ang-II-induced ECM remodeling. Fibulin-2 is required for Ang-II-induced TGF-beta activation in promoting ECM remodeling.
Keywords:cardiac remodeling; fibulin 2; ECM (extracellular molecular);Angiotensin II;TGF-beta
 
 
 

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