The Ski/Zeb2/Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype

Abstract

Background: Cardiac fibrosis is linked to fibroblast to myofibroblast phenoconversion and proliferation; mechanisms underlying this phenoconversion are poorly understood. c-Ski (Ski) is a negative regulator of TGF-β/Smad signaling in myofibroblasts, and may redirect the myofibroblast phenotype back to fibroblasts. Meox2 may alter TGF-β-mediated cellular processes and is repressed by Zeb2. Hypothesis: Ski diminishes the myofibroblast phenotype by de-repressing Meox2 expression and function via repression of Zeb2 expression. Results: Meox1 and Meox2 mRNA expression, Meox2 protein expression are reduced during phenoconversion of fibroblasts to myofibroblasts. Meox2 over-expression shifts the myofibroblasts to fibroblasts, whereas the Meox2 DNA-binding mutant has no effect on myofibroblast phenotype. Ski over-expression partially restores Meox2 mRNA expression levels to those in cardiac fibroblasts. Expression of Zeb2 increased during phenoconversion and Ski over-expression reduces Zeb2 expression in first-passage myofibroblasts. Meox2 expression is decreased in scar following myocardial infarction, whereas Zeb2 protein expression increases in the infarct scar. Thus Ski modulates the cardiac myofibroblast phenotype and function via suppression of Zeb2 by up-regulating Meox2. This cascade may regulate cardiac myofibroblast phenotype and presents therapeutic options for treatment of cardiac fibrosis.