资源描述
,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Adrenomedullin,inhibits vascular calcification,Department of Physiology and,Pathophysiology, Peking University Health Science Center,Key Laboratory of the Ministry of Education on Molecular Cardiology,Yong-Fen Qi,Vascular,calcification,Hypertension,Diabetes,Mellitus,Hyperlipemia,Renal Failure,Aging,Media,Intima,Vascular calcification,is believed to be an important risk factor of cardiovascular,diseases,Atherosclerosis,Vasoactive,peptides:,Adrenomedullin,?,Adrenomedullin,(ADM) is a peptide capable of inducing a potent and long lasting,hypotensive,effect,ADM is mainly synthesized and secreted from vascular endothelial and smooth muscle cells (VSMC),ADM has been shown to have,vasodilatory,hypotensive,and growth regulating properties,Exogenous ADM or ADM gene delivery attenuated hypertension and protected against cardiovascular remodeling, but ADM gene knockout resulted in higher blood pressure and cardiovascular abnormalities.,Endogenous ADM is an important factor in regulating cardiovascular and renal,homoestasis, and is a potent cardio-,reno,-protective factor,receptors bound with ADM were orphan L-1 and RDC-1 receptors,In 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,Fig. 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,).,A,B,45Ca-uptake,(10,3,cpm/mg Pr),Ca content,(,nmol,/mg Pr),ALP activity,(U/mg Pr),Control,32.25.20,46.87.23,7411,Calcified,VSMC,88.210.21*,102.218.23*,62484*,Table :General index of calcified,VSMCs,.( n=6, XS.D.),ALP: alkaline,phosphatase,. *,p,0.01 vs.control.,*,ADM content in,calcified VSMC,ADM mRNA relative,amount in calcified VSMC,CRLR mRNA,RAMP2 mRNA,RAMP3 mRNA,-actin,mRNA,446,bp,416,bp,371,bp,291,bp,C CRLR C RAMP2 C RAMP3,Alterations of CRLR, RAMP2,，,RAMP3 mRNA in calcified,VSMCs,mRNA expression were determined by semi-quantitative RT-PCR analysis. CRLR:,calcitonin,receptor like receptor. RAMP: receptor activity modifying protein. *,p,0.01,compared with control.,*,*,*,*,*,*,*,*,*,*,*,*,Exogenous ADM inhibit calcification of VSMC,Cell counts (10,4,cells/ml),3,H-TdR,(10,3,cpm/mg Pr),3,H-Leu,(10,3,cpm/mg Pr),45,Ca uptake,(10,3,cpm/mg Pr),Calcium content,(,nmol,/mg Pr),ALP activity,(U/mg Pr),Calcifying,10.02,+,1.16,4.86,+,0.52,3.66,+,0.40,169.4,+,13.1,177.4,+,20.0,588,+,67,Ca-ADM IV,8.12,+,0.96,3.32,+,0.28,3.02,+,0.26,126.7,+,11.7,104.5,+,9.7,327,+,28,Ca-ADM IV-PKAI,9.66,+,0.88,#,4.92,+,0.52,#,3.42,+,0.28,#,110.7,+,9.9,#,112.7,+,10.6,317,+,26,#,p,0.05,#,p,0.01, 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 calcification,von,Kossa,staining for myocardium and aorta,A and C: control; B and D: calcified myocardium and aorta respectively,A,B,C,D,control,Calcification,Body Wt, g,28713,24712*,LVW/BW, mg/g,2.490.07,2.70 0.05*,Plasma Ca content,mmol,/L,2.210.10,2.250.08,Heart Ca content, mol/g,dw,2.160.13,9.761.32*,Aortic Ca content, mol/g,dw,11.991.98,84.7612.09*,Myocardial ALP activity, U/mg Pro,153.796.96,255.9983.41*,Aortic ALP activity , U/mg Pro,180.4334.92,329.64105.8*,General characteristics of calcification of myocardium and aorta in rats,control,calcification,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,.,*,*,*,ADM content in plasma, myocardium and aorta,Relative amount of ADM, CRLR, RAMP2 and RAMP3 mRNA,in myocardium and aorta of rats.,*p0.05,*p0.01,vs,control,Myocardium,Aorta,Aorta,Ca(umol/g,dw,),Myocardium Ca,(,umol/g,dw,),Aorta ALP,Activity(U/mg Pro),Control,15.2 1.06,2.41 0.18,46 5.7,VDN,116 8.42*,7.66 0.82*,627 38*,VDN+ADM,78.6 5.17#,4.84 0.42#,371 48#,VDN+Ls,122 8.82,7.22 0.68,597 44,*,p0.05, VDN,vs,control; #p0.05, VDN+ADM,vs,VDN and VDN+Ls,VDN: vitamin D3 plus nicotine; Ls: liposome; ADM:,adrenomedullin,Adrenomedullin,inhibits vascular calcification,#,*,*,p0.05, VDN,vs,control; # p0.01, VDN+ADM,vs,VDN and VDN+Ls,FigB,: The,Scatchard,plots from,125,I-ADM binding with vascular membrane,(-)ADM,(+)ADM,(10,-7,mol/L),Control,1.04 0.08,2.32 0.14,VDN,0.82 0.08*,1.64 0.20*,VDN+ADM,1.58 0.21,#,2.86 0.38,#,VDN+Ls,0.95 0.06,1.98 0.28,Vascular,cAMP,content,Vmax(fmol,/mg),Kd(nmol,/L),Control,833 67,1.4 0.2,VDN,606 52*,2.3 0.3*,VDN+ADM,713 48#,1.5 0.2#,VDN+Ls,522 66,1.8 0.3,Fig. 1. Effect of ADM(2752),on,calcific,nodules in thoracic,aorta of rats (n =7/ group, all,von,Kossa,sections132).,None of,calcific,nodules,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 in,ADM and ADM(2752) rats;,F. less dispersed,calcific,nodules in ADM(2752) rats.,Endogenous ADM was increased, ADM and its receptor gene expressions were,upregulated,in calcified VSMC and aorta,Exogenous ADM can inhibit vascular calcification,Mechanism of ADM inhibiting calcification might be involved in,cAMP,/PKA,pathwasy,Fragments derived from ADM can also inhibit vascular calcification,Summary,Acknowledgements,Chao-shu,Tang,Bin,Geng,Jing,Zhao,Fang Yu,Yong-,zheng,Pang,Bao-hong,Zhang,Chun-,shui,Pan,Da-yong,Cai,Sheng-ying,Wu,Wei,Jiang,Grants:,1. State Major Basic Research Development Program of the Peoples,Republic of China (G2000056905),2. the National Natural Science Foundation of China (30470693),3. the Major Project of the Ministry of Education of,Peoples Republic of China (105001).,4. the Beijing Natural Science Foundation (7052041),
展开阅读全文