Platelet-Derived Growth Factor Receptor β But Not α Mediates Cardiac Fibrosis In Vitro and In Vivo

Abstract

Background: Platelet-derived growth factor (PDGF) is one of the mediators in cardiac fibrosis but its role has not been fully explored. The aim of this study is to investigate the role of PDGF subtypes (AA, AB, BB, & CC) and their receptors (PDGFRα & β) and signalling pathways involved in cardiac fibrosis both in vitro and in vivo. Methods: Cardiac myocyte (NCM) hypertrophy and fibroblast (NCF) collagen synthesis stimulated by PDGF isoforms (10ng/mL) for 48hours, were determined by [3H]-leucine and [3H]-proline incorporation, respectively. Myocardial infarction (MI) was induced 4 weeks after 5/6th subtotal nephrectomy (STNx), following treatment with imidapril (Imid, 10 mg/kg daily) for 8 weeks. At endpoint, cardiac and renal function and structure were examined. Gene expression and Western Blot analysis were performed. Results: Only PDGF AB and BB stimulated NCM hypertrophy and NCF collagen syntheses, and increased hypertrophic, fibrotic and PDGFR gene expression (Fig). PDGF AB and BB activated p38MAPK and Akt, which were inhibited by their selective inhibitors. Imid treatment significantly improved cardiac and renal function, and reduced hypertrophic and fibrotic gene expression, post-STNx+MI. Imid treatment also reversed PDGFRβ and PDGF BB gene expression post-STNx+MI (Fig). Conclusion: The results demonstrated that only PDGF BB and AB via PDGFRβ subtype activation are involved in cardiac fibrosis in vitro and in vivo, suggesting the therapeutic potential of PDGFRβ subtype specific blockade in cardiac fibrosis.