糖尿病與發炎指標糖尿病與發炎指標CRPCRP吳達仁 醫師成大醫學院附設醫院內科部內分泌新陳代謝科 CRP is a symmetrical ring molecule that consists of 5 noncovalent but associate protomers.Each protomer has 2 calcium ions responsible for the specific binding of phosphochlorine.Phosphochlorine is a common constituent of many bacterial and fungal polysaccharides and most biologic cell membranes,such as the phosphochlorine residues of C(or capsular)-polysaccharide of Streptococcus pneumoniae.The protein was named“C-reactive”because of this reaction.A stable pentameric protein-compound with a half-life of 19 hours,without diurnal variation,CRP is a pathogenic marker and a nonspecific marker of inflammation.CRP is synthesized in response to the acute phase of a bacterial or fungal infection.Negatively stained electron micrograph showing the typical pentameric disc-like structure face-on and side-on(arrows).Ribbon diagram of the crystal structure,showing the lectin fold and the two calcium atoms(spheres)in the ligand-binding site of each protomer.Space-filling model of the CRP molecule,showing a single phosphocholine molecule located in the ligand-binding site of each protomer).Pepys MB,et al.Clin Invest 2003;111:1805-1812.During the acute phase of infection,serum CRP levels were measured by rate nephelometry(“serum CRP assay”).These assays have a lower limit of detection of only 6 to 10 mg/l.A more sensitive latex particle-enhanced immunoturbidimetric assay(“high sensitivity hs-CRP assay”)has been developed that has a lower limit of detection(or sensitivity)of about 0.15 mg/l.It is used to assess for cardiovascular risk.The risk factors by hs-CRP levels(CDC,AHA):CRP 1 mg/l is low CVD risk CRP 1 to 3 mg/l is moderate CVD risk CRP 3 to 10 mg/l is high CVD risk CRP levels 10 mg/l generally indicates bacterial infectionMatthias B.et al.Diabetes Care 2004;27:1680-1687.mg/dL n Events1120 1081071 67PlaceboPravastatinRR on Pravastatin =0.65Log rank p=0.002Adjust for on-treatment LDL,HDL,VLDL,TG&baseline covariates.RR on Pravastatin=0.64,p=0.014WOSCOPS Group.Circulation.1998;97:1440-45 The Effects of Atorvastatin versus Simvastatin on Atherosclerosis Progression Study(ASAP)Atorvastatin reduced CRP levels to a greater extent than simvastatinvan Wissen S,et al.Atherosclerosis.2002;165:361-366.*P0.001 for difference between groups;*P=0.02 for difference between groups*-50-45-40-35-30-25-20-15-10-501 Year2 YearsAtorvastatinSimvastatinPercent change in hs-CRP-44.9-14.0-40.1-19.7Influence of Baseline BMI on Ability of Atorvastatin to Modify CV Risk Factors(REVERSAL Study)P0.01P0.01P30)Thrombogenic/hemostatic stateAtherogenic dietNon-modifiableAgeMale sexFamily history of premature CHDNational Cholesterol Education Program Adult Treatment Panel III.2002.NIH Publication No.02-5215.Higher CRP Hypertension Hyperglycemia Low HDL/high TG Smoking Obesity Metabolic syndrome Estrogen/progesterone use Chronic infection Lower CRP Increase exercise Alcohol consumption Weight loss Medication:Statin FibrateKannel W.In:Hypertension:Pathophysiology and Treatment.New York:McGraw-Hill,Inc.;1977:888-909;Castelli WP.Am J Med.1984;76:4-12.CHD incidence/1000Probability of CVD/1000Age40506070Framingham studySBP(mm Hg)in menTC(mg/dL)in menConcomitant Hypertension and Dyslipidemia Increase the Risk of Developing Fatal CVDAdapted from De Backer G et al.Eur J Cardiovasc Prev Rehabil.2003;10(suppl 1):S1-S78.DyslipidemiaHypertensionDyslipidemia/HypertensionTC 271 mg/dL(7 mmol/L)SBP 180 mm HgTC 271 mg/dL(7 mmol/L)SBP 180 mm HgHypertension and High Cholesterol are Twice as Prevalent in Adults with DM Compared to those without DMArchives of Internal Medicine 2002;162:427-433*P0.001Hypertension and Dyslipidemia Commonly Occurs in Diabetes in TaiwanTADE 2002Prevalence(%)High uric acidDyslipidemiaObesityHypertension Ridkor PM.Circulation 1996;97:2007-11.冠冠心心病病風風險險TC/HDL 比值比值CRPC-RP(mg/L)N=1,008肥胖肥胖高血壓高血壓高三酸甘油脂症高三酸甘油脂症低低HDL-C高胰島素血症高胰島素血症Festa et al.Circulation 2000;102:42-7.54321P0.001Albert MA,et al.Circulation.2003;107:443 As early as 1981,a solid-phase single-antibody competitive radioimmunoassay with a single rabbit anti-CRP antibody directly immobilized onto a magnetic particle had a sensitivity of 0.05 mg/l.With use of a double-antibody competitive radioimmunoassay,the sensitivity was increased further to 0.003 mg/l.An in-house ELISA CRP assay developed in 1997 has a sensitivity of 0.007 mg/l and was used in 1999 to evaluate the hs-CRP test for clinical use.In 2000,an immunoradiometric assay(IRMA)was developed with polyclonal antibodies of CRP immobilized on microtiter plates and monoclonal antibodies of CRP labeled with 125I.IRMA had a sensitivity of 0.05 mg/l-36.4*Atorvastatin-5.2PravastatinChange in CRP levels from baseline Change(%)*P0.001 vs pravastatin-40-30-20-1001.82.918 Months2.83.0BaselineAtorvastatinPravastatinCRP(mg/L)Matthias B.et al.Diabetes Care 2004;27:1680-1687.BiomarkerAge adjustedMultivariate adjusted*EstimatePEstimatePHbA1c(%)-0.160.009-0.210.001Total cholesterol(mmol/l)0.050.2910.080.090Triglycerides(mmol/l)-0.450.001-0.390.001HDL cholesterol(mmol/l)0.160.0010.130.001LDL cholesterol(mmol/l)0.080.0540.100.020apoB100(g/l)-0.060.001-0.040.001CRP(mg/l)-0.970.001-0.510.003Fibrinogen(mol/l)-0.870.001-0.530.001sTNFR2(pg/ml)52.820.26289.770.071sICAM-1(ng/ml)-7.810.032-7.560.049sVCAM-1(ng/ml)5.790.75219.120.304Correlation hs-CRP ESR Fibrinogen Chol TG hs-CRP1 ESR0.7470#1 Fibrinogen0.5449*0.8138#1 Chol0.23550.37050.27841 TG-0.0054-0.0077-0.13120.17541 HDL-c0.01000.2480 0.17910.0560-0.3732 Uric acid-0.0107-0.1335-0.1568-0.2308-0.1788 Creatinine-0.2591-0.1355-0.02470.06200.0155Begfore TXBegfore TXAfter TxAfter TxP valueFibrinogen(mg/dl)421 152(403 103)344 81(337 72)P0.001ESR(mm/h)19.1 24.8(16.2 17.0)9.7 8.7(9.4 8.4)P0.01CRP(mg/L)3.3 3.3(3.0 2.6)2.1 1.8(2.0 1.8)P0.01Hb(g/dl)14.0 1.613.9 1.5NSProinsulin(pmol/L)45 1644 15NSWBC(x 103)7.5 1.97.1 1.7NSSeveral reports showed that CRP binds to Fcgamma receptors on leukocytes.CRP(100 microg/mL)significantly upregulated surface expression of Fcgamma receptors,CD32,as well as CD64 on HAECs(P0.01).Preincubation with anti-CD32 and CD64 antibodies significantly inhibited maximal binding of CRP to HAECs 64%and 30%,respectively,whereas antibodies to CD16 had no effect.Internalization of CRP,as determined by loss of surface expression,was 50%.Binding and internalization of biotinylated CRP was confirmed by confocal microscopy and CRP colocalized with CD32 and CD64.Most importantly,the increase in interleukin-8,intercellular adhesion molecule 1,and vascular cell adhesion molecule-1 and the decrease in eNOS and prostacyclin induced by CRP was abrogated with antibodies to CD32 and CD64.CONCLUSIONS:We demonstrate that CRP mediates its biological effects on HAECs via binding and internalization through Fcgamma receptors,CD32 and CD64.DevarajS,etal.ArteriosclerThrombVascBiol.2005;25:1359-63 。