Simvastatin increases fibulin-2 expression in human coronary artery smooth muscle cells via RhoA/Rho-Kinase signaling pathway inhibition

Author, as appears in the article.: Serra, Noem; Rosales, Roser; Masana, Lluis; Vallve, Joan-Carles

Department: Medicina i Cirurgia; Ciències Mèdiques Bàsiques

URV's Author/s: Masana Marín, Luis / ROSALES RIBAS, ROSER / Serra Encinas, Noemi / Vallvé Torrente, Joan Carles

Keywords: Statin therapy; Stabilization; Simvastatin; Signal transduction; Rhoa gtp-binding protein; Rho-associated kinases; Protein fibulin-1; Plaque neovascularization; Myocytes, smooth muscle; Muscle, smooth, vascular; Mechanisms; Matrix; Hydroxymethylglutaryl-coa reductase inhibitors; Humans; Fibulin 2; Extracellular matrix proteins; Disease; Coronary vessels; Collagen content; Cell line; Calcium-binding proteins; Binding; Atherosclerotic plaques

Abstract: © 2015 Serra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The composition and structure of the extracellular matrix (ECM) in the vascular wall and in the atherosclerotic plaque are important factors that determine plaque stability. Statins can stabilize atherosclerotic plaques by modulating ECM protein expression. Fibulins are important components of the ECM. We evaluated the in vitro effect of simvastatin on the expression of fibulin-1, -2, -4 and -5 in human coronary artery smooth muscle cells (SMCs) and the mechanisms involved. Cells were incubated with simvastatin (0.05-1 μM), mevalonate (100 and 200 μM), geranylgeranyl pyrophosphate (GGPP) (15 μM), farnesyl pyrophosphate (FPP) (15 μM), the Rho kinase (ROCK) inhibitor Y-27632 (15 and 20 μM), the Rac-1 inhibitor (another member of Rho family) NSC23766 (100 μM), arachidonic acid (a RhoA/ROCK activator, 25-100 μM) and other fatty acids that are not activators of RhoA/ROCK (25- 100 μM). Gene expression was analyzed by quantitative real-time PCR, and fibulin protein levels were analyzed by western blotting and ELISA. Simvastatin induced a significant increase in mRNA and protein levels of fibulin-2 at 24 hours of incubation (p<0.05), but it did not affect fibulin-1, -4, and -5 expression. Mevalonate and GGPP were able to reverse simvastatin's effect, while FPP did not. In addition, Y-27632, but not NSC23766, significantly increased fibulin-2 expression. Furthermore, activation of the RhoA/ROCK pathway with arachidonic acid decreased fibulin-2 mRNA. Simvastatin increased mRNA levels and protein expression of the ECM protein fibulin-2 through a RhoA and Rho-Kinase-mediated pathway. This increase could affect the composition and structure of the ECM.

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licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 19326203

Author's mail: jc.vallve@urv.cat; noemi.serra@urv.cat; jc.vallve@urv.cat; luis.masana@urv.cat

Record's date: 2025-02-18

Paper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133875

Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/

Paper original source: Plos One. 10 (7): e0133875-

APA: Serra, Noem; Rosales, Roser; Masana, Lluis; Vallve, Joan-Carles (2015). Simvastatin increases fibulin-2 expression in human coronary artery smooth muscle cells via RhoA/Rho-Kinase signaling pathway inhibition. Plos One, 10(7), e0133875-. DOI: 10.1371/journal.pone.0133875

Article's DOI: 10.1371/journal.pone.0133875

Entity: Universitat Rovira i Virgili

Journal publication year: 2015

Publication Type: Journal Publications