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Endothelial Dysfunction in Diabetic Cardiovascular Pathology

This study explores the key role of endothelial progenitor cell deficiency in the cardiovascular pathology of diabetic patients, including impaired fibrinolysis, platelet aggregation, coagulation, permeability, adhesiveness, and inflammation.

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Endothelial Dysfunction in Diabetic Cardiovascular Pathology

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  1. Angelo Avogaro Università degli Studi di Padova Universa Universis Patavina Libertas La carenza di cellule endoteliali progenitrici: un passaggio chiave nell’ambito della patologia cardiovascolare del malato di diabete.

  2. Fibrinolysis Platelets aggregation Coagulation Permeability Adhesiveness Infiammation TXA2 vWF MCP-1 ICAM-1 t-PA Fibrinogen RAGE NO PAI-1 VCAM-1 P-selectin PGI2 TF Thrombomodulin PGI2 VEGF TXA2 PDGF EDHF NO ET-1 TGF-β Vasodilatation Vasocostriction Proliferation

  3. Causes of endothelial dysfunction in Diabetes 1. Impaired  Glucose PKC Polyols AGE Hexosamines NAD(P)H Oxidase ROS ADMA BH4 ROS NOS3 L-arginine L-citrulline NO Glycated proteins ROS NAD(P)H Oxidase  Vasodilatation

  4. Changes in Coronary segment diameters expressed as percentage of baseline in response to Acetylcholine (Adapted from Nitenberg et al. Diabetes 1993) C vs. D P<0.01 P<0.001 P<0.001 P<0.001 n.s

  5. Postprandial Myocardial Perfusion is impaired in Type 2 Diabetic Patients (Scognamiglio et al. 2005) 15 10 Myocardial Blood Flow 5 0 Baseline Postprandial

  6. Changes in Coronary segment diameters expressed as percentage of baseline in response to Acetylcholine (Adapted from Nitenberg et al. Diabetes 1993) C vs. D P<0.01 P<0.001 P<0.001 P<0.001 n.s

  7. Circulating Endothelial Cells in Cardiovascular Disease (Boos et al. 2006) RF RF CEC CD 133+ CD 146- Blood Vessel

  8. Endothelial Precursor Cells: a novel approach to assess vascular integrity 0.1% to 3.0% of endothelial cells proliferate daily Endothelial cell division may reach 50% of the cells in and around the injured sites Ingram et al. Blood 2005

  9. Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA1c (McClung et al. 2005)

  10. Major steps of endothelial cell migration Lamalice, L. et al. Circ Res 2007;100:782-794

  11. EPC Endothelial cell apoptosis and -regeneration Regeneration Apoptosis Risk factors Apoptosis

  12. BoneMarrow↔ CirculatingProgenitorCells CD34+ cell pool Bonemarrowcells Peripheral blood Smooth muscle progenitor cells (a-actin+) Endothelial progenitor cells (KDR+) Cardiomyocyte progenitor cells (c-met+/CXCR4+)

  13. Mechanisms of Progenitor Cell Decrease Defective mobilization Decreased survival Increased homing Deranged differentiation Low EPCs Injured endothelium Repair Apoptosis Ischemia VEGF SDF-1 PlGF FGF EPO EPCs From BONE MARROW Differentiation ? Differentiation HSCs Other CD34+ derived phenotypes New vessel growth VSMCs migration Fadini et al. Curr Diabetes Rev 2005

  14. Bone marrow and peripheral blood progenitor cells Bonemarrow and peripheralbloodsampledduring open heartsurgery r = 0.51 p = 0.017

  15. DiabetesMellitus and EPCs (Tepperet al. Circulation 2002; Loomanset al. Diabetes 2004; Fadiniet al. JACC 2005) Culture EPC count Adhesion HbA1c (%) CTRL DM2 EPC count HbA1c (%)

  16. The quantitative analysis revealed a significant decrease in the CPC amount after culture in HG medium (A) Krankel, N. et al. Arterioscler Thromb Vasc Biol 2005;25:698-703

  17. The clinicalsignificanceofEPCs (Fadiniet al. ATVB 2006) PAD: Disease Stage ofRutheford CCA plaqueobstruction

  18. The clinicalsignificanceofEPCs DiseaseMarker – Prediabetes(Fadiniet al Diabetologia 2007)

  19. Reducedsurvival 120 120 110 110 100 100 90 90 EPC / high power field . EPC / high power field . 80 80 70 70 60 60 50 50 Glucose Glucose 0 25 25 0 25 25 P38 inhib - - + P38 inhib - - + * Seeger et al. Circulation 2005 * * * Federici et al. Diabetes 2006

  20. Impairedmobilization (Fadiniet al. Diabetologia 2006) G-CSF 50 mg/kg + SCF 200 mg/kg 5 days

  21. Progressive progenitor cell decline adjusted observed DM DM DM 10- DM N = 425 NGT IFG IGT new <10 20 >20 200 150 100 50 0 CD34+ Cell count -50 -100 -150 -200 -250 -300 Adjustedforage, sex, plasma glucose, HbA1c, BMI, smoke, bloodpressure, lipidprofile, diabeticcomplications and CVD, medications

  22. CD34+ progenitor cells metabolic components Synergistic reduction of CD34+ progenitors at clustering cardiometabolic risk factors Correlation between CD34+ cells and HOMA, a measure of insulin resistance Fadini et al. Eur Heart J 2006

  23. Progenitor Cells and Outcomes in MetSyn Patients n = 214 All events CV events Death * * After correction for age, sex, lipid profile, blood pressure, family history, smoking habit, obesity, CRP, plasma glucose, renal function, baseline CVD, metabolic syndrome, 10-yr Italian risk score. Atherosclerosis in press

  24. The bone marrow connection DIABETES MELLITUS Endothelial progenitor cells CD34+ Sca-1+ c-kit+ Cardiomyocyte progenitor cells Bone marrow defect Smooth muscle progenitor cells CARDIOVASCULAR COMPLICATIONS

  25. Acknowledgments PADOVA EPC Study Group METABOLIC DIVISION Gianpaolo Fadini Saula de Kreutzenberg GENERAL PATHOLOGY Saverio Sartore Mattia Albiero Stefano Schiaffino CLINICAL IMMUNOLOGY Carlo Agostini Elisa Boscaro Partly supported by the Heart Repair consortium

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