title: Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart.
abstract: Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFRα and PDGFRβ) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRα agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFRα-positive fibroblasts, PDGFRβ agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirus-induced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.
authors: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: Radiosa
authors: R
authors: Gallini
authors: Department of Biotechnology and Molecular Medicine, AI Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
authors: Jenni
authors: J
authors: Huusko
authors: Department of Biotechnology and Molecular Medicine, AI Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
authors: Seppo
authors: S
authors: Ylä-Herttuala
authors: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: Christer
authors: C
authors: Betsholtz
authors: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors: Johanna
authors: J
authors: Andrae
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D006321:Heart / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D020033:Protein Isoforms / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms