title: Global gene expression profiling in PAI-1 knockout murine heart and kidney: molecular basis of cardiac-selective fibrosis.
abstract: Fibrosis is defined as an abnormal matrix remodeling due to excessive synthesis and accumulation of extracellular matrix proteins in tissues during wound healing or in response to chemical, mechanical and immunological stresses. At present, there is no effective therapy for organ fibrosis. Previous studies demonstrated that aged plasminogen activator inhibitor-1 (PAI-1) knockout mice develop spontaneously cardiac-selective fibrosis without affecting any other organs. We hypothesized that differential expressions of profibrotic and antifibrotic genes in PAI-1 knockout hearts and unaffected organs lead to cardiac selective fibrosis. In order to address this prediction, we have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney. Analysis of illumina-based microarray data revealed that several genes involved in different biological processes such as immune system processing, response to stress, cytokine signaling, cell proliferation, adhesion, migration, matrix organization and transcriptional regulation were affected in hearts and kidneys by the absence of PAI-1, a potent inhibitor of urokinase and tissue-type plasminogen activator. Importantly, the expressions of a number of genes, involved in profibrotic pathways including Ankrd1, Pi16, Egr1, Scx, Timp1, Timp2, Klf6, Loxl1 and Klotho, were deregulated in PAI-1 knockout hearts compared to wildtype hearts and PAI-1 knockout kidneys. While the levels of Ankrd1, Pi16 and Timp1 proteins were elevated during EndMT, the level of Timp4 protein was decreased. To our knowledge, this is the first comprehensive report on the influence of PAI-1 on global gene expression profiling in the heart and kidney and its implication in fibrogenesis and several other biological processes. The significance of these observations in the light of heart-specific profibrotic signaling and fibrogenesis are discussed.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America. a-ghosh2@northwestern.edu
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Sheila B
authors.initials: SB
authors.lastname: Murphy
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D051766:Early Growth Response Protein 1; D009124:Muscle Proteins; D009687:Nuclear Proteins; D017395:Plasminogen Activator Inhibitor 1; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; D012097:Repressor Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D000097792:Tissue Inhibitor of Metalloproteinase-4; C104844:Ankrd1 protein, mouse; C486109:Egr1 protein, mouse; C524777:protease inhibitor 16, mouse