Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression

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Acosta , A J , Rysä , J , Szabo , Z , Moilanen , A-M , Komati , H , Nemer , M & Ruskoaho , H 2017 , ' Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression ' , Cell and Tissue Research , vol. 367 , no. 2 , pp. 369-385 . https://doi.org/10.1007/s00441-016-2527-2

Title: Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression
Author: Acosta, Alicia Jurado; Rysä, Jaana; Szabo, Zoltan; Moilanen, Anne-Mari; Komati, Hiba; Nemer, Mona; Ruskoaho, Heikki
Other contributor: University of Helsinki, Faculty of Pharmacy



Date: 2017-02
Language: eng
Number of pages: 17
Belongs to series: Cell and Tissue Research
ISSN: 0302-766X
DOI: https://doi.org/10.1007/s00441-016-2527-2
URI: http://hdl.handle.net/10138/309273
Abstract: The phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of endothelin-1 and alpha(1)-adrenergic signaling in cardiac hypertrophy. However, the role of PEX1 in transcriptional regulation of myocardial remodeling remains largely unknown. In the present study, we used PEX1 gain- and loss-of-function to examine the effects of PEX1 on left ventricular remodeling. Adenoviral constructs expressing PEX1, antisense PEX1, or LacZ were delivered by local injection into the anterior wall of the left ventricle in Sprague-Dawley rats. PEX1 overexpression led to induction of hypertrophic gene program and increased fibrosis. In agreement with this, the expression of genes involved in the fibrotic process, such as collagens I and III, matrix metalloproteinases (MMPs), fibronectin-1, transforming growth factor beta-1 and connective tissue growth factor, were significantly up-regulated following PEX1 overexpression, whereas silencing of PEX1 significantly inhibited the expression of pro-fibrotic genes and increased left ventricular ejection fraction and fractional shortening. In vitro luciferase reporter assays showed that PEX1 regulates the expression of MMP-9 by activating promoter. Furthermore, PEX1 gain- and loss-of-function experiments in rat neonatal cardiac fibroblasts and myocytes revealed that MMP-9 gene expression was affected by PEX1 predominantly in fibroblasts. Our results indicate that PEX1 is involved in regulating cardiac fibrosis and extracellular matrix turnover, particularly fibroblasts being responsible for the fibrosis-associated changes in gene expression. Furthermore, PEX1 activation of the MMP-9 promoter triggers the pro-fibrotic response directed by PEX1.
Subject: Fibrosis
Hypertrophy
Myocardial remodeling
Signal transduction
Transcription factor
MYOCARDIAL-INFARCTION
HEART-FAILURE
TGF-BETA
CARDIAC FIBROBLASTS
DIASTOLIC DYSFUNCTION
NUCLEAR MEDIATOR
CELL-SURFACE
ADULT HEART
MATRIX-METALLOPROTEINASE-9
FIBROSIS
1182 Biochemistry, cell and molecular biology
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