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PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
Gothenburg Univ, Sahlgrenska Acad, Dept Med Biochem, Gothenburg, Sweden.;AstraZeneca R&D, Molndal, Sweden..
Gothenburg Univ, Sahlgrenska Acad, Dept Med Biochem, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
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2016 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 349, no 2, p. 282-290Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfra in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFR alpha agonists supports a role for endogenous PDGFRa agonists in the pathogenesis of cardiac fibrosis.

Place, publisher, year, edition, pages
2016. Vol. 349, no 2, p. 282-290
Keywords [en]
PDGF, Transgene, Myosin heavy chain, Fibrosis, Heart
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-312037DOI: 10.1016/j.yexcr.2016.10.022ISI: 000389163200009PubMedID: 27816607OAI: oai:DiVA.org:uu-312037DiVA, id: diva2:1062375
Funder
Swedish Cancer SocietySwedish Research CouncilNovo NordiskKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseAvailable from: 2017-01-05 Created: 2017-01-04 Last updated: 2018-05-18Bibliographically approved

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