Ex Vivo Evidence for the Contribution of Hemodynamic Shear Stress Abnormalities to the Early Pathogenesis of Calcific Bicuspid Aortic Valve Disease 英文参考文献.docVIP

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Ex Vivo Evidence for the Contribution of Hemodynamic Shear Stress Abnormalities to the Early Pathogenesis of Calcific Bicuspid Aortic Valve Disease 英文参考文献.doc

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Ex Vivo Evidence for the Contribution of Hemodynamic Shear Stress Abnormalities to the Early Pathogenesis of Calcific Bicuspid Aortic Valve Disease 英文参考文献

ExVivoEvidencefortheContributionofHemodynamic ShearStressAbnormalitiestotheEarlyPathogenesisof CalcificBicuspidAorticValveDisease LingSun1,2,SantanuChandra1,PhilippeSucosky1,2* 1Department ofAerospace and Mechanical Engineering, University of Notre Dame, Notre Dame,Indiana, United States of America, 2Eck Institute for Global Health, UniversityofNotreDame,NotreDame,Indiana,UnitedStatesofAmerica Abstract Thebicuspidaorticvalve(BAV)isthemostcommoncongenitalcardiacanomalyandisfrequentlyassociatedwithcalcific aortic valve disease (CAVD). The most prevalent type-I morphology, which results from left-/right-coronary cusp fusion, generatesdifferenthemodynamicsthanatricuspidaorticvalve(TAV).Whilevalvularcalcificationhasbeenlinkedtogenetic and atherogenic predispositions, hemodynamic abnormalities are increasingly pointed as potential pathogenic contributors. In particular, the wall shear stress (WSS) produced by blood flow on the leaflets regulates homeostasis in theTAV.Incontrast,WSSalterationscausevalvedysfunctionanddisease.Whilesuchobservationssupporttheexistenceof synergies between valvular hemodynamics and biology, the role played by BAV WSS in valvular calcification remains unknown. The objective of this study was to isolate the acute effects of native BAV WSS abnormalities on CAVD pathogenesis.PorcineaorticvalveleafletsweresubjectedexvivotothenativeWSSexperiencedbyTAVandtype-IBAV leaflets for 48hours. Immunostaining, immunoblotting and zymography were performed to characterize endothelial activation,pro-inflammatoryparacrinesignaling,extracellularmatrixremodelingandmarkersinvolvedinvalvularinterstitial cellactivationandosteogenesis.WhileTAVandnon-coronaryBAVleafletWSSessentiallymaintainedvalvularhomeostasis, fusedBAVleafletWSSpromotedfibrosaendothelialactivation,paracrinesignaling(2.4-foldand3.7-foldincreaseinBMP-4 andTGF-b1,respectively,relativetofreshcontrols),catabolicenzymesecretion(6.3-fold,16.8-fold,11.7-fold,16.7-foldand 5.5-fold increase in MMP-2, MMP-9,