Transfection of mouse cardiac fibroblasts with miR-29b targeted fibrosis-related proteins and attenuated the response to TGF-β, while miR-30c had little effect on extracellular matrix production.
Does modulation of miR-29b and miR-30c alter extracellular matrix secretion and cardiac fibrosis in preclinical models?
Proteomic analysis reveals that miR-29b and miR-30c have distinct roles in regulating extracellular matrix secretion and cardiac fibrosis, highlighting novel molecular targets for fibrogenic cardiac phenotypes.
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.
Abonnenc et al. (Thu,) conducted a other in Cardiac fibrosis. pre-/anti-miR of miR-29b and miR-30c was evaluated on Extracellular matrix secretion by cardiac fibroblasts. Transfection of mouse cardiac fibroblasts with miR-29b targeted fibrosis-related proteins and attenuated the response to TGF-β, while miR-30c had little effect on extracellular matrix production.
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