title: Secreted Frizzled-related protein 2 as a target in antifibrotic therapeutic intervention.
abstract: Progressive fibrosis is a pathological hallmark of many chronic diseases responsible for organ failure. Although there is currently no therapy on the market that specifically targets fibrosis, the dynamic fibrogenic process is known to be regulated by multiple soluble mediators that may be therapeutically intervened. The failing hamster heart exhibits marked fibrosis and increased expression of secreted Frizzled-related protein 2 (sFRP2) amenable to reversal by mesenchymal stem cell (MSC) therapy. Given the previous demonstration that sFRP2-null mice subjected to myocardial infarction exhibited reduced fibrosis and improved function, we tested whether antibody-based sFRP2 blockade might counteract the fibrogenic pathway and repair cardiac injury. Cardiomyopathic hamsters were injected intraperitoneally twice a week each with 20 μg of sFRP2 antibody. Echocardiography, histology, and biochemical analyses were performed after 1 mo. sFRP2 antibody increased left ventricular ejection fraction from 40 ± 1.2 to 49 ± 6.5%, whereas saline and IgG control exhibited a further decline to 37 ± 0.9 and 31 ± 3.2%, respectively. Functional improvement is associated with a ∼ 50% reduction in myocardial fibrosis, ∼ 65% decrease in apoptosis, and ∼ 75% increase in wall thickness. Consistent with attenuated fibrosis, both MSC therapy and sFRP2 antibody administration significantly increased the activity of myocardial matrix metalloproteinase-2. Gene expression analysis of the hamster heart and cultured fibroblasts identified Axin2 as a downstream target, the expression of which was activated by sFRP2 but inhibited by therapeutic intervention. sFRP2 blockade also increased myocardial levels of VEGF and hepatocyte growth factor (HGF) along with increased angiogenesis. These findings highlight the pathogenic effect of dysregulated sFRP2, which may be specifically targeted for antifibrotic therapy.
authors: Department of Biochemistry and Department of Biomedical Engineering, Center for Research in Cardiovascular Medicine, University at Buffalo, Buffalo, New York.
authors: Michalis
authors: M
authors: Mastri
authors: Zaeem
authors: Z
authors: Shah
authors: Karin
authors: K
authors: Hsieh
authors: Xiaowen
authors: X
authors: Wang
authors: Bailey
authors: B
authors: Wooldridge
authors: Sean
authors: S
authors: Martin
authors: Gen
authors: G
authors: Suzuki
authors: Techung
authors: T
authors: Lee
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology; D060466:Axin Protein / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D005355:Fibrosis; D006321:Heart; D006333:Heart Failure / Q000378:metabolism / Q000628:therapy*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D013318:Stroke Volume / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000906:Antibodies; D060466:Axin Protein; D017228:Hepatocyte Growth Factor; D020778:Matrix Metalloproteinase 2; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins
keywords: MMP; VEGF; fibrosis; heart failure; sFRP2