title: Macrophages derived from septic mice modulate nitric oxide synthase and angiogenic mediators in the heart.
abstract: Macrophages (Mps) can exert the defense against invading pathogens. During sepsis, bacterial lipopolisaccharide (LPS) activates the production of inflammatory mediators by Mps. Nitric oxide synthase (NOS) derived-nitric oxide (NO) is one of them. Besides, Mps may produce pro-angiogenic molecules such as vascular endothelial growth factor-A (VEGF-A) and metalloproteinases (MMPs). The mechanisms involved in the cardiac neovascular response by Mps during sepsis are not completely known. We investigated the ability of LPS-treated Mps from septic mice to modulate the behavior of cardiac cells as producers of NO and angiogenic molecules. In vivo LPS treatment (0.1 mg/mouse) increased NO production more than fourfold and induced de novo NOS2 expression in Mps. Immunoblotting assays also showed an induction in VEGF-A and MMP-9 expression in lysates obtained from LPS-treated Mps, and MMP-9 activity was detected by zymography in cell supernatants. LPS-activated Mps co-cultured with normal heart induced the expression of CD31 and VEGF-A in heart homogenates and increased MMP-9 activity in the supernatants. By immunohistochemistry, we detected new blood vessel formation in hearts cultured with LPS treated Mps. When LPS-stimulated Mps were co-cultured with isolated cardiomyocytes in a transwell assay, the expression of NOS2, VEGF-A and MMP-9 was induced in cardiac cells. In addition, MMP-9 activity was up-regulated in the supernatant of cardiomyocytes. The latter was due to NOS2 induction in Mps from in vivo LPS-treated mice. In conclusion LPS-treated Mps are inducers of inflammatory/angiogenic mediators in cardiac cells, which could be triggering neovascularization, as an attempt to improve cardiac performance in sepsis.
authors: Centro de Estudios Farmacológicos y Botánicos-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Eulalia
authors: E
authors: de la Torre
authors: Eugenia
authors: E
authors: Hovsepian
authors: Federico N
authors: FN
authors: Penas
authors: Ganna
authors: G
authors: Dmytrenko
authors: María E
authors: ME
authors: Castro
authors: Nora B
authors: NB
authors: Goren
authors: Maria E
authors: ME
authors: Sales
mesh_terms: D000818:Animals; D005260:Female; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019001:Nitric Oxide Synthase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse