Relaxin Signals through a RXFP1-pERK-nNOS-NO-cGMP-Dependent Pathway to Up-Regulate Matrix Metalloproteinases The Additional Involvement of iNOS 英文参考文献.docVIP

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Relaxin Signals through a RXFP1-pERK-nNOS-NO-cGMP-Dependent Pathway to Up-Regulate Matrix Metalloproteinases The Additional Involvement of iNOS 英文参考文献.doc

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Relaxin Signals through a RXFP1-pERK-nNOS-NO-cGMP-Dependent Pathway to Up-Regulate Matrix Metalloproteinases The Additional Involvement of iNOS 英文参考文献

RelaxinSignalsthroughaRXFP1-pERK-nNOS-NO-cGMP- DependentPathwaytoUp-RegulateMatrix Metalloproteinases:TheAdditionalInvolvementofiNOS BrynaSuetManChow1,2,ElaineGuoYanChew1¤,ChongxinZhao1,RossA.D.Bathgate1,2, TimD.Hewitson3,4*,ChrishanS.Samuel1,2,5 * 1Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia, 2Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia, 3Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia, 4Department of Medicine, University of Melbourne, RoyalMelbourneHospital,Parkville,Victoria,Australia,5DepartmentofPharmacology,MonashUniversity,Clayton,Victoria,Australia Abstract The hormone, relaxin, inhibits aberrant myofibroblast differentiation and collagen deposition by disrupting the TGF-b1/ Smad2axis,viaitscognatereceptor,RelaxinFamilyPeptideReceptor1(RXFP1),extracellularsignal-regulatedkinase(ERK)1/ 2phosphorylation(pERK)andaneuronalnitricoxide(NO)synthase(nNOS)-NO-cyclicguanosinemonophosphate(cGMP)- dependentpathway.However,thesignallingpathwaysinvolvedinitsadditionalabilitytoincreasematrixmetalloproteinase (MMP)expressionandactivityremainunknown.ThisstudyinvestigatedtheextenttowhichtheNOpathwaywasinvolved inhumangene-2(H2)relaxin’sabilitytopositivelyregulateMMP-1anditsrodentorthologue,MMP-13,MMP-2andMMP-9 (the main collagen-degrading MMPs) in TGF-b1-stimulated human dermal fibroblasts and primary renal myofibroblasts isolated from injured rats; by gelatin zymography (media) and Western blotting (cell layer). H2 relaxin (10–100ng/ml) significantlyincreasedMMP-1(by,50%),MMP-2(by,80%)andMMP-9(by,80%)inTGF-b1-stimulatedhumandermal fibroblasts;andMMP-13(by,90%),MMP-2(by,130%)andMMP-9(by,115%)inratrenalmyofibroblasts(allp,0.01vs untreatedcells)over72hours.Therelaxin-inducedup-regulationoftheseMMPs,however,wassignificantlyblockedbya non-selective NOS inhibitor (L-nitroarginine methyl ester (hydrochloride); L-NAME; 75–100 mM), and specifi