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.
Highlights
In response to injury, the body’s defense system immediately responds leading to induction of inflammation which is an essential event during wound healing
Results revealed that while myocardial tissues derived from 12-month old Plasminogen activator inhibitor-1 (PAI-1) knockout mice showed modest accumulation of collagen compared to age-matched wildtype controls (Wildtype 12 m 0.005760.0015 vs. PAI-1 knockout 12 m 0.054160.0248; p = 0.09), myocardial tissues derived from 24month old PAI-1 knockout mice showed significantly elevated levels of collagen accumulation compared to age- and sex-matched wildtype controls (Wildtype 24 m 0.014360.006 vs. PAI-1 knockout 24 m 0.154660.0144; p = 0.0004) (Figure 2A–D)
Previous studies demonstrated that aged plasminogen activator inhibitor-1 (PAI-1) knockout mice develop cardiac-selective fibrosis without affecting any other organs [8,9,10]
Summary
The body’s defense system immediately responds leading to induction of inflammation which is an essential event during wound healing. Vascular injury causes mononuclear cell infiltration/inflammation in affected organs. The infiltrating cells produce a wide variety of cytokines including the profibrotic cytokine TGF-ß that activates fibroblast migration to the injury site. Activated fibroblasts undergo differentiation to myofibroblasts that synthesize collagen and other extracellular matrix proteins and play a pivotal role in wound healing [1,2,3,4]. Unchecked wound healing leads to loss of tissue homeostasis due to excessive synthesis and deposition of collagens by activated myofibroblasts in the wound area, a pathological manifestation of organ fibrosis [1,2,3,4,5,6]. Previous studies demonstrated that aged PAI-1 knockout mice develop cardiac-specific fibrosis without affecting any other organ [8,9,10] and provide an excellent animal model for identification of factor(s) that ignite(s) organ-specific fibrosis
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