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Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c.
- Source :
-
Circulation research [Circ Res] 2013 Oct 25; Vol. 113 (10), pp. 1138-47. Date of Electronic Publication: 2013 Sep 04. - Publication Year :
- 2013
-
Abstract
- Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis.<br />Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix secretion by cardiac fibroblasts.<br />Methods and Results: Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry. miR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor, insulin-like growth factor 1, and pentraxin 3, 3 predicted targets of miR-29b. miR-29b also attenuated the cardiac fibroblast response to transforming growth factor-β. In contrast, miR-30c had little effect on extracellular matrix production but opposite effects regarding leukemia inhibitory factor and insulin-like growth factor 1. Both miRNAs indirectly affected cardiac myocytes. On transfection with pre-miR-29b, the conditioned medium of cardiac fibroblasts lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (α-actinin, cardiac myosin-binding protein C, and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium, whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c, and miR-30c, but not miR-29b, were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function.<br />Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.
- Subjects :
- Animals
C-Reactive Protein metabolism
Cells, Cultured
Collagen metabolism
Fibroblasts cytology
Fibroblasts drug effects
Fibrosis
Insulin-Like Growth Factor I metabolism
Leukemia Inhibitory Factor metabolism
Male
Matrix Metalloproteinases metabolism
Mice
Mice, Inbred C57BL
Models, Animal
Myocardium pathology
Serum Amyloid P-Component metabolism
Transforming Growth Factor beta pharmacology
Extracellular Matrix metabolism
Fibroblasts metabolism
MicroRNAs physiology
Myocardium metabolism
Proteomics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 113
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 24006456
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.113.302400