Transforming growth factor-beta inhibition reduces progression of early choroidal neovascularization lesions in rats: P17 and P144 peptides
The purpose of this study was to assess the effects of transforming growth factor beta (TGF-β) inhibitor peptides (P17 & P144) on early laser-induced choroidal neovascularization (LI-CNV) lesions in rats, two weeks after laser CNV induction. Seventy-one Long Evans rats underwent diode laser appl...
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| Veröffentlicht in: | PloS one 2013-05, Vol.8 (5), p.e65434 |
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| description | The purpose of this study was to assess the effects of transforming growth factor beta (TGF-β) inhibitor peptides (P17 & P144) on early laser-induced choroidal neovascularization (LI-CNV) lesions in rats, two weeks after laser CNV induction. Seventy-one Long Evans rats underwent diode laser application in an established LI-CNV model. Baseline fluorescein angiography (FA) was performed 14 days following laser procedure, and treatments were administered 16 days post-laser application via different administration routes. Intravenous groups included control (IV-Control), P17 (IV-17), and P144 (IV-144) groups, whereas intravitreal groups included P17 (IVT-17), P144 (IVT-144), and a mixture of both peptides (IVT-17+144) (with fellow eyes receiving vehicle alone). CNV evolution was assessed using FA performed weekly for four weeks after treatment. Following sacrifice, VEGF, TGF-β, COX-2, IGF-1, PAI-1, IL-6, MMP-2, MMP-9, and TNF-α gene expression was assessed using RT-PCR. VEGF and p-SMAD2 protein levels were also assessed by western-blot, while MMP-2 activity was assessed with gelatin zymography. Regarding the FA analysis, the mean CNV area was lower from the 3(rd) week in IVT-17 and IVT-144 groups, and also from the 2(nd) week in IVT-17+144. Biochemical analysis revealed that gene expression was lower for VEGF and COX-2 genes in IV-17 and IV-144 groups, VEGF gene in IVT-17+144 group and MMP-2 gene in IVT-17 and IVT-144 groups. VEGF protein expression was also decreased in IV-17, IV-144, IVT-17 and IVT-144, whereas pSMAD-2 levels were lower in IV-17, IV-144 and IVT-17+144 groups. Zymogram analysis revealed decreased MMP-2 activity in IV-17, IV-144, IVT-17 and IVT-144 groups. These data suggest that the use of TGF-β inhibitor peptides (P17 & P144) decrease the development of early CNV lesions by targeting different mediators than those typically affected using current anti-angiogenic therapies. Its potential role in the treatment of early CNV appears promising as a single therapy or adjuvant to anti-VEGF drugs. |
| doi_str_mv | 10.1371/journal.pone.0065434 |
| format | Article |
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Seventy-one Long Evans rats underwent diode laser application in an established LI-CNV model. Baseline fluorescein angiography (FA) was performed 14 days following laser procedure, and treatments were administered 16 days post-laser application via different administration routes. Intravenous groups included control (IV-Control), P17 (IV-17), and P144 (IV-144) groups, whereas intravitreal groups included P17 (IVT-17), P144 (IVT-144), and a mixture of both peptides (IVT-17+144) (with fellow eyes receiving vehicle alone). CNV evolution was assessed using FA performed weekly for four weeks after treatment. Following sacrifice, VEGF, TGF-β, COX-2, IGF-1, PAI-1, IL-6, MMP-2, MMP-9, and TNF-α gene expression was assessed using RT-PCR. VEGF and p-SMAD2 protein levels were also assessed by western-blot, while MMP-2 activity was assessed with gelatin zymography. Regarding the FA analysis, the mean CNV area was lower from the 3(rd) week in IVT-17 and IVT-144 groups, and also from the 2(nd) week in IVT-17+144. Biochemical analysis revealed that gene expression was lower for VEGF and COX-2 genes in IV-17 and IV-144 groups, VEGF gene in IVT-17+144 group and MMP-2 gene in IVT-17 and IVT-144 groups. VEGF protein expression was also decreased in IV-17, IV-144, IVT-17 and IVT-144, whereas pSMAD-2 levels were lower in IV-17, IV-144 and IVT-17+144 groups. Zymogram analysis revealed decreased MMP-2 activity in IV-17, IV-144, IVT-17 and IVT-144 groups. These data suggest that the use of TGF-β inhibitor peptides (P17 & P144) decrease the development of early CNV lesions by targeting different mediators than those typically affected using current anti-angiogenic therapies. Its potential role in the treatment of early CNV appears promising as a single therapy or adjuvant to anti-VEGF drugs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0065434</identifier><identifier>PMID: 23741494</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age ; Angiogenesis ; Angiography ; Animals ; Biochemical analysis ; Biology ; Choroidal Neovascularization - drug therapy ; Choroidal Neovascularization - metabolism ; Choroidal Neovascularization - pathology ; Cyclooxygenase 2 - genetics ; Cyclooxygenase 2 - metabolism ; Cyclooxygenase-2 ; Cytokines ; Data processing ; Disease Progression ; Drugs ; Fluorescein ; Fluorescein Angiography ; Gelatin ; Gelatinase A ; Gelatinase B ; Gene expression ; Gene Expression Regulation - drug effects ; Hypotheses ; Inhibitors ; Insulin-like growth factor I ; Insulin-like growth factors ; Interleukin 6 ; Intravenous administration ; Laboratories ; Laser applications ; Lasers ; Lesions ; Macular degeneration ; Male ; Matrix Metalloproteinase 2 - metabolism ; Medicine ; Membranes ; Peptide Fragments - administration & dosage ; Peptide Fragments - pharmacology ; Peptides ; Peptides - administration & dosage ; Peptides - pharmacology ; Phosphorylation - drug effects ; Polyamide-imides ; Polymerase chain reaction ; Rats ; Receptors, Transforming Growth Factor beta - administration & dosage ; Retina ; Rodents ; Smad2 protein ; Smad2 Protein - metabolism ; Studies ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming Growth Factor beta - metabolism ; Transforming growth factor-b ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascularization</subject><ispartof>PloS one, 2013-05, Vol.8 (5), p.e65434</ispartof><rights>2013 Zarranz-Ventura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Zarranz-Ventura et al 2013 Zarranz-Ventura et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-8b8e6754d1d77c06be056ea0ddbb6cfc2017a6189252306c3b9819826babd233</citedby><cites>FETCH-LOGICAL-c592t-8b8e6754d1d77c06be056ea0ddbb6cfc2017a6189252306c3b9819826babd233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669249/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669249/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23741494$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Vavvas, Demetrios</contributor><creatorcontrib>Zarranz-Ventura, Javier</creatorcontrib><creatorcontrib>Fernández-Robredo, Patricia</creatorcontrib><creatorcontrib>Recalde, Sergio</creatorcontrib><creatorcontrib>Salinas-Alamán, Angel</creatorcontrib><creatorcontrib>Borrás-Cuesta, Francisco</creatorcontrib><creatorcontrib>Dotor, Javier</creatorcontrib><creatorcontrib>García-Layana, Alfredo</creatorcontrib><title>Transforming growth factor-beta inhibition reduces progression of early choroidal neovascularization lesions in rats: P17 and P144 peptides</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The purpose of this study was to assess the effects of transforming growth factor beta (TGF-β) inhibitor peptides (P17 & P144) on early laser-induced choroidal neovascularization (LI-CNV) lesions in rats, two weeks after laser CNV induction. Seventy-one Long Evans rats underwent diode laser application in an established LI-CNV model. Baseline fluorescein angiography (FA) was performed 14 days following laser procedure, and treatments were administered 16 days post-laser application via different administration routes. Intravenous groups included control (IV-Control), P17 (IV-17), and P144 (IV-144) groups, whereas intravitreal groups included P17 (IVT-17), P144 (IVT-144), and a mixture of both peptides (IVT-17+144) (with fellow eyes receiving vehicle alone). CNV evolution was assessed using FA performed weekly for four weeks after treatment. Following sacrifice, VEGF, TGF-β, COX-2, IGF-1, PAI-1, IL-6, MMP-2, MMP-9, and TNF-α gene expression was assessed using RT-PCR. VEGF and p-SMAD2 protein levels were also assessed by western-blot, while MMP-2 activity was assessed with gelatin zymography. Regarding the FA analysis, the mean CNV area was lower from the 3(rd) week in IVT-17 and IVT-144 groups, and also from the 2(nd) week in IVT-17+144. Biochemical analysis revealed that gene expression was lower for VEGF and COX-2 genes in IV-17 and IV-144 groups, VEGF gene in IVT-17+144 group and MMP-2 gene in IVT-17 and IVT-144 groups. VEGF protein expression was also decreased in IV-17, IV-144, IVT-17 and IVT-144, whereas pSMAD-2 levels were lower in IV-17, IV-144 and IVT-17+144 groups. Zymogram analysis revealed decreased MMP-2 activity in IV-17, IV-144, IVT-17 and IVT-144 groups. These data suggest that the use of TGF-β inhibitor peptides (P17 & P144) decrease the development of early CNV lesions by targeting different mediators than those typically affected using current anti-angiogenic therapies. Its potential role in the treatment of early CNV appears promising as a single therapy or adjuvant to anti-VEGF drugs.</description><subject>Age</subject><subject>Angiogenesis</subject><subject>Angiography</subject><subject>Animals</subject><subject>Biochemical analysis</subject><subject>Biology</subject><subject>Choroidal Neovascularization - drug therapy</subject><subject>Choroidal Neovascularization - metabolism</subject><subject>Choroidal Neovascularization - pathology</subject><subject>Cyclooxygenase 2 - genetics</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cyclooxygenase-2</subject><subject>Cytokines</subject><subject>Data processing</subject><subject>Disease Progression</subject><subject>Drugs</subject><subject>Fluorescein</subject><subject>Fluorescein Angiography</subject><subject>Gelatin</subject><subject>Gelatinase A</subject><subject>Gelatinase B</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Hypotheses</subject><subject>Inhibitors</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-like growth factors</subject><subject>Interleukin 6</subject><subject>Intravenous administration</subject><subject>Laboratories</subject><subject>Laser applications</subject><subject>Lasers</subject><subject>Lesions</subject><subject>Macular degeneration</subject><subject>Male</subject><subject>Matrix Metalloproteinase 2 - 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administration & dosage</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides</topic><topic>Peptides - administration & dosage</topic><topic>Peptides - pharmacology</topic><topic>Phosphorylation - drug effects</topic><topic>Polyamide-imides</topic><topic>Polymerase chain reaction</topic><topic>Rats</topic><topic>Receptors, Transforming Growth Factor beta - administration & dosage</topic><topic>Retina</topic><topic>Rodents</topic><topic>Smad2 protein</topic><topic>Smad2 Protein - metabolism</topic><topic>Studies</topic><topic>Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Transforming growth factor-b</topic><topic>Tumor necrosis factor-TNF</topic><topic>Tumor necrosis factor-α</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zarranz-Ventura, Javier</creatorcontrib><creatorcontrib>Fernández-Robredo, Patricia</creatorcontrib><creatorcontrib>Recalde, Sergio</creatorcontrib><creatorcontrib>Salinas-Alamán, Angel</creatorcontrib><creatorcontrib>Borrás-Cuesta, Francisco</creatorcontrib><creatorcontrib>Dotor, Javier</creatorcontrib><creatorcontrib>García-Layana, Alfredo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zarranz-Ventura, Javier</au><au>Fernández-Robredo, Patricia</au><au>Recalde, Sergio</au><au>Salinas-Alamán, Angel</au><au>Borrás-Cuesta, Francisco</au><au>Dotor, Javier</au><au>García-Layana, Alfredo</au><au>Vavvas, Demetrios</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transforming growth factor-beta inhibition reduces progression of early choroidal neovascularization lesions in rats: P17 and P144 peptides</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-05-31</date><risdate>2013</risdate><volume>8</volume><issue>5</issue><spage>e65434</spage><pages>e65434-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The purpose of this study was to assess the effects of transforming growth factor beta (TGF-β) inhibitor peptides (P17 & P144) on early laser-induced choroidal neovascularization (LI-CNV) lesions in rats, two weeks after laser CNV induction. Seventy-one Long Evans rats underwent diode laser application in an established LI-CNV model. Baseline fluorescein angiography (FA) was performed 14 days following laser procedure, and treatments were administered 16 days post-laser application via different administration routes. Intravenous groups included control (IV-Control), P17 (IV-17), and P144 (IV-144) groups, whereas intravitreal groups included P17 (IVT-17), P144 (IVT-144), and a mixture of both peptides (IVT-17+144) (with fellow eyes receiving vehicle alone). CNV evolution was assessed using FA performed weekly for four weeks after treatment. Following sacrifice, VEGF, TGF-β, COX-2, IGF-1, PAI-1, IL-6, MMP-2, MMP-9, and TNF-α gene expression was assessed using RT-PCR. VEGF and p-SMAD2 protein levels were also assessed by western-blot, while MMP-2 activity was assessed with gelatin zymography. Regarding the FA analysis, the mean CNV area was lower from the 3(rd) week in IVT-17 and IVT-144 groups, and also from the 2(nd) week in IVT-17+144. Biochemical analysis revealed that gene expression was lower for VEGF and COX-2 genes in IV-17 and IV-144 groups, VEGF gene in IVT-17+144 group and MMP-2 gene in IVT-17 and IVT-144 groups. VEGF protein expression was also decreased in IV-17, IV-144, IVT-17 and IVT-144, whereas pSMAD-2 levels were lower in IV-17, IV-144 and IVT-17+144 groups. Zymogram analysis revealed decreased MMP-2 activity in IV-17, IV-144, IVT-17 and IVT-144 groups. These data suggest that the use of TGF-β inhibitor peptides (P17 & P144) decrease the development of early CNV lesions by targeting different mediators than those typically affected using current anti-angiogenic therapies. Its potential role in the treatment of early CNV appears promising as a single therapy or adjuvant to anti-VEGF drugs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23741494</pmid><doi>10.1371/journal.pone.0065434</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-05, Vol.8 (5), p.e65434 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1357395158 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Age Angiogenesis Angiography Animals Biochemical analysis Biology Choroidal Neovascularization - drug therapy Choroidal Neovascularization - metabolism Choroidal Neovascularization - pathology Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Cyclooxygenase-2 Cytokines Data processing Disease Progression Drugs Fluorescein Fluorescein Angiography Gelatin Gelatinase A Gelatinase B Gene expression Gene Expression Regulation - drug effects Hypotheses Inhibitors Insulin-like growth factor I Insulin-like growth factors Interleukin 6 Intravenous administration Laboratories Laser applications Lasers Lesions Macular degeneration Male Matrix Metalloproteinase 2 - metabolism Medicine Membranes Peptide Fragments - administration & dosage Peptide Fragments - pharmacology Peptides Peptides - administration & dosage Peptides - pharmacology Phosphorylation - drug effects Polyamide-imides Polymerase chain reaction Rats Receptors, Transforming Growth Factor beta - administration & dosage Retina Rodents Smad2 protein Smad2 Protein - metabolism Studies Transforming Growth Factor beta - antagonists & inhibitors Transforming Growth Factor beta - metabolism Transforming growth factor-b Tumor necrosis factor-TNF Tumor necrosis factor-α Vascular endothelial growth factor Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism Vascularization |
| title | Transforming growth factor-beta inhibition reduces progression of early choroidal neovascularization lesions in rats: P17 and P144 peptides |
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