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AdrenomedullininhibitsvascularcalcificationDepartmentofPhysiologyandPathophysiology,PekingUniversityHealthScienceCenterKeyLaboratoryoftheMinistryofEducationonMolecularCardiologyYong-FenQi2020/10/181AdrenomedullininhibitsvascuVascular calcificationHypertensionDiabetes Mellitus HyperlipemiaRenal Failure Aging MediaIntima Vascular calcification is believed to be an important risk factor of cardiovasculardiseasesAtherosclerosis2020/10/182VascularHypertensionDiabetesVasoactive peptides:Adrenomedullin?2020/10/183Vasoactivepeptides:?2020/10/1nAdrenomedullin(ADM)is a peptide capable of inducing a potent and long lasting hypotensive effect nADM is mainly synthesized and secreted from vascular endothelial and smooth muscle cells(VSMC)nADM has been shown to have vasodilatory,hypotensive and growth regulating properties,nExogenous ADM or ADM gene delivery attenuated hypertension and protected against cardiovascular remodeling,but ADM gene knockout resulted in higher blood pressure and cardiovascular abnormalities.nEndogenous ADM is an important factor in regulating cardiovascular and renal homoestasis,and is a potent cardio-reno-protective factor2020/10/184Adrenomedullin(ADM)isapeptnreceptors bound with ADM were orphan L-1 and RDC-1 receptors nIn addition,another orphan receptor named calcitonin receptor-like receptor(CRLR)could bind with ADM when receptor activity-modifying protein(RAMP)2 and/or RAMP3 existed on cellular membrane surface 2020/10/185receptorsboundwithADMwereFig.1.(A)Calcification of multicellular nodules.von Kossa staining for calcification,showing positive staining as black/brown areas within the main,large,nodular structure(original magnification 40).(B)Formation of multicellular nodules in culture phase contrast microscopy showing rat VSMCs(original magnification 20).AB2020/10/186Fig.1.(A)Calcificationofm45Ca-uptake(103cpm/mgPr)Cacontent(nmol/mgPr)ALPactivity(U/mgPr)Control32.25.2046.87.237411CalcifiedVSMC88.210.21*102.218.23*62484*Table:General index of calcified VSMCs.(n=6,XS.D.)ALP:alkaline phosphatase.*p0.01 vs.control.2020/10/18745Ca-uptakeCacontentALPact*ADM content in calcified VSMCADM mRNA relative amount in calcified VSMCCRLR mRNARAMP2 mRNARAMP3 mRNA-actin mRNA446 bp416 bp371 bp291 bpC CRLR C RAMP2 C RAMP3AlterationsofCRLR,RAMP2，RAMP3mRNAincalcifiedVSMCsmRNAexpressionweredeterminedbysemi-quantitativeRT-PCRanalysis.CRLR:calcitoninreceptorlikereceptor.RAMP:receptoractivitymodifyingprotein.*p0.01,comparedwithcontrol.2020/10/188*ADMcontentinADMmRNAre*Exogenous ADM inhibit calcification of VSMC2020/10/189*Exogenous2020/10/18102020/10/1810Cell counts(104cells/ml)3H-TdR(103cpm/mg Pr)3H-Leu(103cpm/mg Pr)45Ca uptake(103cpm/mg Pr)Calcium content(nmol/mg Pr)ALP activity(U/mg Pr)Calcifying 10.02+1.164.86+0.52 3.66+0.40 169.4+13.1 177.4+20.0588+67 Ca-ADM IV 8.12+0.963.32+0.28 3.02+0.26 126.7+11.7 104.5+9.7 327+28Ca-ADM IV-PKAI 9.66+0.88#4.92+0.52#3.42+0.28#110.7+9.9#112.7+10.6317+26#p0.05,#p0.01,compared with the group having the same peptide but no inhibitor.Calcifying:calcifying alone group;Ca-:calcifying;ADM:Adrenomedullin.PKAI:protein kinase A inhibitor.Effects of protein kinase A inhibitor on vascular calcification2020/10/1811Cellcounts(104cells/ml)3H-TvonKossastainingformyocardiumandaortaAandC:control;BandD:calcifiedmyocardiumandaortarespectivelyABCD2020/10/1812vonKossastainingformyocardcontrol Calcification Body Wt,g2871324712*LVW/BW,mg/g2.490.072.70 0.05*Plasma Ca content,mmol/L2.210.10 2.250.08Heart Ca content,mol/g dw 2.160.13 9.761.32*Aortic Ca content,mol/g dw11.991.98 84.7612.09*Myocardial ALP activity,U/mg Pro153.796.96 255.9983.41*Aortic ALP activity,U/mg Pro 180.4334.92329.64105.8*Generalcharacteristicsofcalcificationofmyocardiumandaortainrats2020/10/1813controlCalcificationBodyWt,controlcalcification MBP,mmHg 1047 1092 LVEDP,mmHg 4.621.60 5.101.23+LVdp/dtmax,mmHg/s 4386304 3977276*HR,beats/min 41417 41415-LVdp/dtmax,mmHg/s 4033387 3227315*Blood pressure and cardiac function of control and vascular calcification of rat.2020/10/1814controlcalcificationMBP,mmHg*ADM content in plasma,myocardium and aorta2020/10/1815*ADMcontentinplasma,myRelativeamountofADM,CRLR,RAMP2andRAMP3mRNAinmyocardiumandaortaofrats.*p0.05,*p0.01vscontrolMyocardiumAorta2020/10/1816RelativeamountofADM,CRLR,Aorta Ca(umol/g dw)Myocardium Ca(umol/g dw)Aorta ALPActivity(U/mg Pro)Control15.2 1.062.41 0.1846 5.7VDN116 8.42*7.66 0.82*627 38*VDN+ADM78.6 5.17#4.84 0.42#371 48#VDN+Ls122 8.827.22 0.68597 44*p0.05,VDNvscontrol;#p0.05,VDN+ADMvsVDNandVDN+LsVDN:vitaminD3plusnicotine;Ls:liposome;ADM:adrenomedullinAdrenomedullin inhibits vascular calcification#*p0.05,VDNvscontrol;#p0.01,VDN+ADMvsVDNandVDN+Ls2020/10/1817AortaCa(umol/gdw)MyocardiumFigB:The Scatchard plots from 125I-ADM binding with vascular membrane(-)ADM(+)ADM(10-7mol/L)Control1.04 0.082.32 0.14VDN0.82 0.08*1.64 0.20*VDN+ADM1.58 0.21#2.86 0.38#VDN+Ls0.95 0.061.98 0.28Vascular cAMP content Vmax(fmol/mg)Kd(nmol/L)Control833 671.4 0.2VDN606 52*2.3 0.3*VDN+ADM713 48#1.5 0.2#VDN+Ls522 661.8 0.32020/10/1818FigB:TheScatchardplotsfromFig.1.Effect of ADM(2752)on calcific nodules in thoracic aorta of rats(n=7/group,all von Kossa sections132).A.None of calcific nodules B.in control rats;B.dispersed calcific nodules in model rats;C.dense calcific nodules in model rats;D.less dispersed calcific nodules in ADM rats;E.lest calcific nodules inADM and ADM(2752)rats;F.less dispersed calcific nodules in ADM(2752)rats.2020/10/1819Fig.1.EffectofADM(2752)202020/10/18202020/10/18202020/10/18212020/10/1821nEndogenous ADM was increased,ADM and its receptor gene expressions were upregulated in calcified VSMC and aortanExogenous ADM can inhibit vascular calcificationnMechanism of ADM inhibiting calcification might be involved in cAMP/PKA pathwasy nFragments derived from ADM can also inhibit vascular calcificationSummary2020/10/1822EndogenousADMwasincreased,谢谢您的聆听与观看THANK YOU FOR YOUR 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