Unique Cardiac Fibroblast Expression Profiles in Pathological and Physiological Hypertrophy

The heart undergoes hypertrophic growth in response to both physiological and pathological stimuli. Pathological hypertrophy results from various humoral, mechanical, or ischemic insults, and often leads to cardiac fibrosis, diminished contractility, and heart failure. In contrast, physiological hypertrophy is an adaptive response to the excessive demands of exercise or pregnancy and does not lead to fibrosis. We hypothesized that cardiac fibroblasts, the main cellular source of extracellular matrix in the heart, exhibit distinct expression profiles in physiological or pathological remodeling that influence the divergent fibrotic response. To investigate these differences, we obtained the expression profile of cardiac fibroblasts isolated from mice subjected to swim training, pressure-overload induced cardiac remodeling, or myocardial infarction by RNA-sequencing. Although we observed cardiac growth in all conditions, pressure-overload induced hypertrophy and myocardial infarction induced the predicted fibrotic gene expression signature, which was absent in physiological hypertrophy. Utilizing these validated datasets, we identified novel genes and molecular pathways that are differentially expressed in physiological and pathological hypertrophic remodeling and will correlate transcriptional programs with altered gene profiles. Fibroblast gene expression profiles in pathological and physiological are expected to lead to diagnostic or prognostic markers of fibrotic remodeling as well as genes that may serve as novel therapeutic strategies to prevent or reverse cardiac fibrosis.