title: Peroxisome proliferator-activated receptor-gamma ligands attenuate brain natriuretic peptide production and affect remodeling in cardiac fibroblasts in reoxygenation after hypoxia.
abstract: Cardiac fibroblasts (CFs) participate in cardiac remodeling after hypoxic cardiac damage, and remodeling is thought to be mediated by CF synthesis of brain natriuretic peptide (BNP). It is unknown whether the peroxisome proliferator-activated receptors (PPARs), which mediate cellular signaling for growth and migration, affect BNP synthesis and whether PPARs participate in regulation of extracellular matrix protein (ECM) expression for remodeling. We examined the production of BNP in cultured neonatal ventricular CFs and its signaling system on collagen synthesis and on activation of matrix metalloproteinases (MMPs) in reoxygenation after hypoxia. BNP mRNA was detected in CFs, and a specific BNP protein, BNP1-32, was secreted into the media. Abundance of collagen I and III was increased in the media at reoxygenation. mRNA and protein levels for MMP-2 and the tissue inhibitor of metalloproteinase (TIMP)-1 were enhanced in CFs at reoxygenation. These observations also were noted in CFs after incubation with angiotensin II (10 microM) for 24 h. Pretreatment with pioglitaozone (0.1-10 microM) attenuated BNP mRNA and protein abundance of collagen III, MMP-2, and TIMP-1 in CFs at reoxygenation. The secreted BNP was also decreased by pioglitaozone in the media. Furthermore, PPAR activators inhibited reoxygenation-induced activation of nuclear factor (NF)-kappaB. These results demonstrate that PPAR activators inhibit BNP synthesis in CFs and imply that PPAR activators may regulate ECM remodeling partially through the NF-kappaB-mediated pathway.
authors.affiliation: Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan. makino@tsurumi.beppu.kyushu-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Makino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sugano
authors.forename: Shinji
authors.initials: S
authors.lastname: Satoh
authors.forename: Junichi
authors.initials: J
authors.lastname: Oyama
authors.forename: Toyoki
authors.initials: T
authors.lastname: Maeda
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D024042:Collagen Type I; D024061:Collagen Type III; D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D019715:Tissue Inhibitor of Metalloproteinase-1; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015230:Prostaglandin D2; D010100:Oxygen; D000077205:Pioglitazone