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Defining the cellular repertoire of GPCRs identifies a profibrotic role for the most highly expressed receptor, protease‐activated receptor 1, in cardiac fibroblasts
Author(s) -
Snead Aaron N.,
Insel Paul A.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-213496
Subject(s) - g protein coupled receptor , receptor , thrombin , biology , myofibroblast , microbiology and biotechnology , gene knockdown , fibrosis , cardiac fibrosis , phenotype , signal transduction , immunology , medicine , cell culture , genetics , gene , platelet
G‐protein‐coupled receptors (GPCRs) have many roles in cell regulation and are commonly used as drug targets, but the repertoire of GPCRs expressed by individual cell types has not been defined. Here we use an unbiased approach, GPCR RT‐PCR array, to define the expression of nonchemosensory GPCRs by cardiac fibroblasts (CFs) isolated from Rattus norvegicus. CFs were selected because of their importance for cardiac structure and function and their contribution to cardiac fibrosis, which occurs with advanced age, after acute injury ( e.g. , myocardial infarction), and in disease states ( e.g. , diabetes mellitus, hypertension). We discovered that adult rat CFs express 190 GPCRs and that activation of protease‐activated receptor 1 (PAR1), the most highly expressed receptor, raises the expression of profibrotic markers in rat CFs, resulting in a 60% increase in collagen synthesis and conversion to a profibrogenic myofibroblast phenotype. We use siRNA knockdown of PAR1 (90% decrease in mRNA) to show that the profibrotic effects of thrombin are PAR1‐dependent. These findings, which define the expression of GPCRs in CFs, provide a proof of principle of an approach to discover previously unappreciated, functionally relevant GPCRs and reveal a potential role for thrombin and PAR1 in wound repair and pathophysiology of the adult heart.—Snead, A. N., Insel, P. A. Defining the cellular repertoire of GPCRs identifies a profibrotic role for the most highly expressed receptor, protease‐activated receptor 1, in cardiac fibroblasts. FASEB J. 26, 4540–4547 (2012). www.fasebj.org