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

Abonnenc, Mélanie, Nabeebaccus, Adam A., Mayr, Ursula, Barallobre-Barreiro, Javier, Dong, Xuebin, Cuello, Friederike, Sur, Sumon, Drozdov, Ignat, Langley, Sarah R. ORCID: https://orcid.org/0000-0003-4419-476X, Lu, Ruifang, Stathopoulou, Konstantina, Didangelos, Athanasios, Yin, Xiaoke, Zimmermann, Wolfram-Hubertus, Shah, Ajay M., Zampetaki, Anna and Mayr, Manuel 2013. Extracellular matrix secretion by cardiac fibroblasts: role of microRNA-29b and microRNA-30c. Circulation Research 113 (10) , pp. 1138-1147. 10.1161/circresaha.113.302400

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Heart Association
ISSN:	0009-7330
Last Modified:	05 Sep 2023 13:31
URI:	https://orca.cardiff.ac.uk/id/eprint/162144

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