Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression.
The phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of endothelin-1 and α1-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.
Department of Pharmacology and Toxicology, Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, POB 5000, 90014, Oulu, Finland.
Alicia
A
Jurado Acosta
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211, Kuopio, Finland.
Jaana
J
Rysä
Department of Pharmacology and Toxicology, Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, POB 5000, 90014, Oulu, Finland.
Zoltan
Z
Szabo
Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland.|Oulu University Hospital and Medical Research Center Oulu, POB 5000, 90014, Oulu, Finland.
Anne-Mari
AM
Moilanen
Molecular Genetics and Cardiac Regeneration Laboratory, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, K1H8M5, Ontario, Canada.
Hiba
H
Komati
Molecular Genetics and Cardiac Regeneration Laboratory, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, K1H8M5, Ontario, Canada.
Mona
M
Nemer
Department of Pharmacology and Toxicology, Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, POB 5000, 90014, Oulu, Finland. heikki.ruskoaho@helsinki.fi.|Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, POB 56, 00014, Helsinki, Finland. heikki.ruskoaho@helsinki.fi.
Heikki
H
Ruskoaho
D000256:Adenoviridae / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006973:Hypertension / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism*
D008565:Membrane Proteins; C000619557:PEX1 protein, rat; D014157:Transcription Factors; D000804:Angiotensin II; D020780:Matrix Metalloproteinase 9
Fibrosis; Hypertrophy; Myocardial remodeling; Signal transduction; Transcription factor