Abstract 16089: Pulmonary Hypertension-Induced Right Ventricular Pressure Overload Stimulates Cardiac Fibroblast Periostin Expression and Dedifferentiation of Adult Cardiac Myocytes.

Our group has previously reported that conditioned media derived from cardiac fibroblasts (Cfib) from the pulmonary hypertensive (PH)-right ventricle (RV) causes rapid and marked dedifferentiation of adult cardiac myocytes. However, the factor(s) responsible for dedifferentiation remain unidentified. Periostin, a 90kDa secreted protein, is nearly undetectable in the healthy adult heart, but is selectively re-expressed by fibroblasts following pressure overload. Periostin has been reported to stimulate cardiomyocyte cell cycle re-entry and regeneration, but its role in dedifferentiation is unknown, despite the observation that dedifferentiation is required for adult myocyte regeneration. We performed mass spectrometric analysis of the PH-RV Cfib secretome and identified that periostin is significantly upregulated compared to control (CO-RV). RNA-seq analysis also suggested higher expression of periostin in the PH-RV Cfib. qRT-PCR confirmed periostin to be upregulated nearly 8-fold compared to CO-RV. At the protein level, periostin expression was significantly upregulated in isolated PH-RV Cfib, but not in whole PH-RV homogenates, suggesting a Cfib-specific regulation and expression of periostin. In support of this hypothesis, immunohistochemical staining of the PH-RV demonstrated localization of periostin in the interstitial space, with little to no expression in the cardiomyocyte. Together, these data support the hypothesis that Cfib from the PH-RV synthesize and secrete periostin, contributing to myocyte dedifferentiation through a Cfib-cardiomyocyte axis. Ongoing experiments will test this hypothesis using biochemical, immunodepletion, and genetic approaches. [ABSTRACT FROM AUTHOR]