C‐Ski upregulation of Meox2 diminishes cardiac myofibroblast phenotype

Abstract

Cardiac fibroblast phenoconversion to myofibroblasts (characterized by up-regulation of α-smooth muscle actin (α-SMA), non-muscle myosin heavy chain b (SMemb), and ED-A fibronectin) is induced by a number of ligands, including transforming growth factor β1 (TGF-β1). TGF-β1 signal is transduced through Smad proteins to increase expression of extracellular matrix proteins leading to: expansion of the cardiac interstitium, stiffened myocardium and loss of optimal cardiac pump function. Meox proteins bind Smads and may modulate TGF-β1 functions while c-Ski is a TGF-β1 inhibitor. Herein we investigated the effects of c-Ski and Meox proteins on cardiac myofibroblast phenotype. We observed a reduction in both Meox1 and Meox2 mRNA expression between P0 (primary cardiac fibroblast) and P2 (myofibroblast) cells. We found a significant diminution of myofibroblast phenotype marker protein expression (α-SMA and ED-A fibronectin) in cells over-expressing c-Ski. Remarkably, exogenous c-Ski induced a 6-fold increase in Meox2 mRNA expression, with no change in Meox1. Meox2 over-expression, independent of c-Ski overexpression, induced a reduction in the myofibroblast markers α-SMA and ED-A fibronectin. We suggest that c-Ski “rescues” the quiescent fibroblastic phenotype via up-regulation of Meox2 (Supported by the Heart and Stroke Foundation of Manitoba and the Canadian Institutes for Health Research).