Preferential Activation of SMAD158 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6 英文参考文献.docVIP

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Preferential Activation of SMAD158 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6 英文参考文献.doc

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Preferential Activation of SMAD158 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6 英文参考文献

PreferentialActivationofSMAD1/5/8ontheFibrosa EndotheliuminCalcifiedHumanAorticValves- AssociationwithLowBMPAntagonistsandSMAD6 RandallF.Ankeny1,VinodH.Thourani2,DaianaWeiss3,J.DavidVega2,W.RobertTaylor1,3,RobertM. Nerem4,HanjoongJo1,3,5* 1WallaceH.CoulterDepartmentofBiomedicalEngineering,GeorgiaInstituteofTechnologyandEmoryUniversity,Atlanta,Georgia,UnitedStatesofAmerica,2Division of Cardiothoracic Surgery, Emory University, Atlanta, Georgia, United States of America, 3Division of Cardiology, Emory University, Atlanta, Georgia, United States of America,4Petit Institute for Bioengineering and Bioscience, Georgia Institute ofTechnology, Atlanta, Georgia,United States of America, 5Department ofBioinspired Science,EwhaWoman’sUniversity,Seoul,Korea Abstract Background: Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relativelyunaffected.Here,wetestedthehypothesisthatside-dependentactivationofbonemorphogenicprotein(BMP) pathwayintheendotheliumoftheventricularisandfibrosaisassociatedwithhumanAVcalcification. Methods and Results: Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFbpathway)didnotshowanydifference.Interestingly,wefoundthatBMP-2/4/6expressionwassignificantlyhigheron the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium comparedtothefibrosainbothdiseasestates.Moreover,significantexpressionofinhibitorySMAD-6expressionwasfound onlyinthenon-calcifiedventricularisendothelium. Conclusions:SMAD-1/5/8ispreferentiallyactivatedinthecalcifiedfibrosaendotheliumofh