Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator

التفاصيل البيبلوغرافية
العنوان: Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator
المؤلفون: A. R. Plawman, April Stempien-Otero, David A. Dichek, Goro Otsuka, Teja Dyamenahalli, Jessica Meznarich
المصدر: Journal of Biological Chemistry. 281:15345-15351
بيانات النشر: Elsevier BV, 2006.
سنة النشر: 2006
مصطلحات موضوعية: medicine.medical_specialty, Plasmin, Cardiac fibrosis, Mice, Transgenic, Receptors, Cell Surface, Matrix metalloproteinase, Biochemistry, Receptors, Urokinase Plasminogen Activator, Mice, Fibrosis, Internal medicine, medicine, Animals, Humans, Macrophage, Receptor, Molecular Biology, Mice, Knockout, Chemistry, Macrophages, Myocardium, Heart, Plasminogen, Cell Biology, medicine.disease, Urokinase-Type Plasminogen Activator, Mice, Inbred C57BL, Urokinase receptor, Endocrinology, Verapamil, Gelatinases, cardiovascular system, medicine.drug
الوصف: Human hearts with end-stage failure and fibrosis have macrophage accumulation and elevated plasminogen activator activity. However, the mechanisms that link macrophage accumulation and plasminogen activator activity with cardiac fibrosis are unclear. We previously reported that mice with macrophage-targeted overexpression of urokinase plasminogen activator (SR-uPA+/o mice) develop cardiac macrophage accumulation by 5 weeks of age and cardiac fibrosis by 15 weeks. We used SR-uPA+/o mice to investigate mechanisms through which macrophage-expressed uPA causes cardiac macrophage accumulation and fibrosis. We hypothesized that: 1) macrophage accumulation and cardiac fibrosis in SR-uPA+/o mice are dependent on localization of uPA by the uPA receptor (uPAR); 2) activation of plasminogen by uPA and subsequent activation of transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase (MMP)-2 and -9 by plasmin are critical pathways through which uPA-expressing macrophages accumulate in the heart and cause fibrosis; and 3) uPA-induced cardiac fibrosis can be attenuated by treatment with verapamil. To test these hypotheses, we bred the SR-uPA+/o transgene into mice deficient in either uPAR or plasminogen and measured cardiac macrophage accumulation and fibrosis. We also measured cardiac TGF-beta1 protein (total and active), Smad2 phosphorylation, and MMP activity after the onset of macrophage accumulation but before the onset of cardiac fibrosis. Finally, we treated mice with verapamil. Our studies revealed that plasminogen is necessary for uPA-induced cardiac fibrosis and macrophage accumulation but uPAR is not. We did not detect plasmin-mediated activation of TGF-beta1, MMP-2, or MMP-9 in hearts of SR-uPA+/o mice. However, verapamil treatment significantly attenuated both cardiac fibrosis and macrophage accumulation.
تدمد: 0021-9258
DOI: 10.1074/jbc.m512818200
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa8e1c3ea7fb330d240f35a44fd007b3
https://doi.org/10.1074/jbc.m512818200
Rights: OPEN
رقم الانضمام: edsair.doi.dedup.....fa8e1c3ea7fb330d240f35a44fd007b3
قاعدة البيانات: OpenAIRE
الوصف
تدمد:00219258
DOI:10.1074/jbc.m512818200