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Circ Res. 2013 Oct 25;113(10):1138-47. doi: 10.1161/CIRCRESAHA.113.302400. Epub 2013 Sep 4.

Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c.

Author information

1
From the King's British Heart Foundation Centre, King's College London, London, United Kingdom.

Abstract

RATIONALE:

MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis.

OBJECTIVE:

To perform a proteomics comparison of miRNA effects on extracellular matrix secretion by cardiac fibroblasts.

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.

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.

KEYWORDS:

animal models; cardiovascular disease; fibroblasts; fibrosis; microRNAs; proteomics

PMID:
24006456
DOI:
10.1161/CIRCRESAHA.113.302400
[Indexed for MEDLINE]

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