The role of P2Y2 receptor activation in pro‐fibrotic responses of cardiac fibroblasts

Abstract

Cardiac fibroblasts (CFs) play an essential structural role in the heart and in cardiac remodeling after injury. CFs are activated and adopt a pro‐fibrotic phenotype in response to a variety of growth factors including extracellular nucleotides. Such nucleotides can interact with 8 known P2Y receptors, G‐protein‐coupled receptors (GPCRs); P2Y2 receptors (P2Y2R), which are activated by ATP and UTP, are the most abundant P2Y receptor expressed by rat cardiac fibroblasts. In this study we examined the effect of UTP on fibroblast transformation. UTP dose‐dependently increased the expression of pro‐fibrotic markers, including plasminogen activator inhibitor‐1, transforming growth factor‐ß and α‐smooth muscle actin. In addition, UTP increased proliferation and migration of CFs. Effects similar to those induced by UTP occurred with the non‐hydrolyzable analog UTPγS. The stimulatory effects of UTP on pro‐fibrotic gene expression and CF proliferation did not occur in CF from P2Y2R‐knockout mice. Thus, UTP promotes CF transformation to a pro‐fibrotic phenotype through activation of P2Y2R. Our results suggest that UTP and other extracellular nucleotides (e.g. ATP) may act via P2Y2R to regulate CF activation and migration during normal and injury‐induced cardiac remodeling.Supported by grants from NIH (GM007752, HL066941, GM066232) and the Ellison Medical Fdn.