Overexpression of HTRA1 Leads to Ultrastructural Changes in the Elastic Layer of Bruchs Membrane via Cleavage of Extracellular Matrix Components 英文参考文献.docVIP

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Overexpression of HTRA1 Leads to Ultrastructural Changes in the Elastic Layer of Bruchs Membrane via Cleavage of Extracellular Matrix Components 英文参考文献.doc

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Overexpression of HTRA1 Leads to Ultrastructural Changes in the Elastic Layer of Bruchs Membrane via Cleavage of Extracellular Matrix Components 英文参考文献

OverexpressionofHTRA1LeadstoUltrastructural ChangesintheElasticLayerofBruch’sMembranevia CleavageofExtracellularMatrixComponents SarahVierkotten,PhilippS.Muether,SaschaFauser* CenterofOphthalmology,UniversityofCologne,Cologne,Germany Abstract Variants in the chromosomal region 10q26 are strongly associated with an increased risk for age-related macular degeneration (AMD). Two potential AMD genes are located in this region: ARMS2 and HTRA1 (high-temperature requirement A1). Previous studies have suggested that polymorphisms in the promotor region of HTRA1 result in overexpressionofHTRA1protein.ThisstudyinvestigatedtheroleofHTRA1overexpressioninthepathogenesisofAMD. TransgenicHtra1miceoverexpressingthemurineproteinintheretinalpigmentepithelium(RPE)layeroftheretinawere generatedandcharacterizedbytransmissionelectronmicroscopy,immunofluorescencestainingandWesternBlotanalysis. TheelasticlayerofBruch’smembrane(BM)intheHtra1transgenicmicewasfragmentedandlesscontinuousthaninwild type(WT)controls.RecombinantHTRA1lackingtheN-terminaldomaincleavedvariousextracellularmatrix(ECM)proteins. Subsequent Western Blot analysis revealed an overexpression of fibronectin fragments and a reduction of fibulin 5 and tropoelastin in the RPE/choroid layer in transgenic mice compared to WT. Fibulin 5 is essential for elastogenesis by promotingelasticfiberassemblyandmaturation.Takentogether,ourdataimplicatethatHTRA1overexpressionleadstoan altered elastogenesis in BM through fibulin 5 cleavage. It highlights the importance of ECM related proteins in the developmentofAMDandlinksHTRA1tootherAMDriskgenessuchasfibulin5,fibulin6,ARMS2andTIMP3. Citation: Vierkotten S, Muether PS, Fauser S (2011) Overexpression of HTRA1 Leads to Ultrastructural Changes in the Elastic Layer of Bruch’s Membrane via CleavageofExtracellularMatrixComponents.PLoSONE6(8):e22959.doi:10.1371/journal.pone.0022959 Editor:AlfredLewin,UniversityofFlorida,UnitedStatesofAmerica ReceivedApril6,2011;AcceptedJuly2,2011;PublishedAugus