Scleraxis over‐expression promotes the cardiac myofibroblast phenotype (1152.13)

Abstract

Myofibroblasts are the primary mediators of cardiac remodeling, and their persistence in the myocardium is implicated in the development of fibrosis. Thus, inhibiting myofibroblast differentiation represents a novel approach for treating cardiac fibrosis. Scleraxis is a transcription factor required for development of collagen rich tissues. Interestingly, the same stimuli that induce differentiation also cause increased scleraxis levels in vitro and in vivo. Thus, we hypothesized that scleraxis promotes the myofibroblast phenotype. To test this, we over‐expressed scleraxis via adenovirus in primary cardiac fibroblasts (CFs) and measured changes in key myofibroblast markers. We observed that scleraxis over‐expression in CFs caused increased mRNA and protein levels of these markers. Since myofibroblasts are also distinguished from fibroblasts by their contractility, we used a contraction assay to determine the functional implications of increased marker levels. We found that over‐expressing scleraxis in CFs caused a significant increase in contraction. However, over‐expression of a dominant negative DNA binding‐deficient scleraxis mutant did not induce contraction, indicating a requirement for intact scleraxis. These results demonstrate that scleraxis promotes the cardiac myofibroblast phenotype, implicating scleraxis as a potential target for the intervention of cardiac fibrosis.Grant Funding Source: Supported by Canadian Institute of Healthy Research, St. Boniface Hospital Foundation