Αντιαθηρογόνες και καρδιοπροστατευτικές δράσεις της HDL

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1 ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΔΠΜΣ Ιατρική Χημεία Αντιαθηρογόνες και καρδιοπροστατευτικές δράσεις της HDL Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχημείας Κλινικής Χημείας

2 Incidence of CAD (per 1000 in 6 years) HDL is a major factor in predicting CAD 120 n=4, < >55 HDL-cholesterol (mg/dl) Assmann G, et al. Atherosclerosis. 1996;124(suppl):S11-S20

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5 Αντιαθηρογόνος ρόλος της HDL

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8 Major steps in the reverse cholesterol transport pathway Brousseau M

9 Eστεροποίηση της Χοληστερόλης από την LCAT

10 Ρόλος της LCAT στην ωρίμανση της HDL

11 Cholesterol Delivery to the Liver A-I FC CE SR-B1 A-I Can participate in RCT again (or alternately cleared by kidney)

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13 HDL Prevents Foam Cell Formation

14 HDL Inhibits LDL Oxidative Modification

15 HDL Inhibits Adhesion Molecule Expression

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17 HDL components expressing biological activities Lp-PLA 2 (PAF-AH) PON-1 Apo A-I LCAT Minor phospolipids

18 Removal of seeding molecules from LDL by apo AI Navab M et al, JLR 2000; 41: 1481

19 Antioxidant and antiinflammatory effect of apo AI in vivo Navab M et al, JLR 2000; 41: 1481

20 Antiatherogenic effect of an apo AI mimetic peptide in vivo Navab M et al, Circulation 2002; 105: 290

21 Υδρόλυση των οξειδωμένων φωσφολιπιδίων από τις PAF-AH και PON-1

22 Effect of PON-1 on LDL oxidation Rosenblat M, et al. JBC 2006; 281: 7657

23 Effect of PON-1 on HDL-mediated macrophage cholesterol efflux Rosenblat M, et al. JBC 2006; 281: 7657

24 Effect of adenovirus-mediated expression of PAF-AH on spontaneous atherosclerosis in apoe-/- mice Quarck R, et al. Circulation 2001; 103: 2495

25 Effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation in apoe-/- mice Ox-LDL Quarck R, et al. Circulation 2001; 103: 2495

26 Effect of adenovirus-mediated expression of PAF-AH on endothelial adhesiveness in apoe-/- mice Theilmeier G, et al. FASEB J 2000; 14: 2032

27 Hyperglycemia and Oxidative stress induce dysfunctional HDL HOCl-HDL Kontush A, et al. Pharmacol Rev 58: , 2006

28 Endothelial Cells Macrophage Macrophage HDL HOCl oxhdl (HOCl-HDL)

29 Formation of Gly-ox-LDL and Gly-ox-HDL

30 Μεταβολή των αντιοξειδωτικών και αντιφλεγμονωδών ιδιοτήτων της HDL

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33 Inflammatory/Antiinflammatory Properties of HDL in CAD Ansell B, et al Circulation 2003; 108:2751

34 The inflammatory/antiinflammatory properties of HDL distinguish CAD patients from controls better than serum HDL-cholesterol levels Ansell B, et al Circulation 2003; 108:2751

35 HDL A new potential therapeutic target for the prevention of CVD

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37 ΥΓΙΕΙΝΟΔΙΑΙΤΗΤΙΚΗ ΑΓΩΓΗ ΚΑΙ ΑΥΞΗΣΗ ΤΗΣ HDL-CHOL Διακοπή καπνίσματος Απώλεια βάρους Σωματική άσκηση Μικρές ποσότητες οινοπνεύματος Δίαιτα

38 Therapy to raise HDL-C Bhatt KN, et al. Curr Treat Options Cardiov Med (2010) 12:

39 Specific Specific Impact Impact of of CETP Activity Triglycerides go from VLDL to HDL VLDL CE TG TG CETP A-I CE Result: Cholesterol gets shuttled back into apo B pathway, HDL-C levels go down Cholesterol goes from HDL to VLDL FC CE HDL-CHOL

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41 Seetharam D, et al. Circ Res 2006; 98:63 ApoA-I and HDL promote reendothelialization

42 Helical wheel representation and space-filling models of peptide 4F Antioxidant and antiinflammatory activities of peptide 4F Datta G, et al. JBC 2004; 279: 26509

43 Representative cross-sectional intravascular ultrasound images of matched arterial segments at baseline (left) and follow-up (right) Rec human apoa-i Milano Nicholls SJ, et al. JACC 2006; 47:992

44 IVUS images of coronary plaque before and 5 weeks after once weekly intravenous injection of (rapoa-i Milano, A- Im, ETC-216) in ACS patients Shah PK, et al. Am J Cardiol 2007;100[suppl]:62N 67N

45 A single intravenous injection of rapoa-i M phospholipid complex reduces aortic plaque lipid and inflammation within 48h in apoe KO mice Shah PK, et al. Am J Cardiol 2007;100[suppl]:62N 67N

46 Atheroprotective effects of wild-type apoa-i versus apoa-i Milano gene transfer in apoe/apoa-i double KO mice Shah PK, et al. Am J Cardiol 2007;100[suppl]:62N 67N

47 Synthesis of biomimetic HDL using a Au NP core for use as a therapeutic Luthi AJ, et al. Trends Mol Med. 2010, 16,

48 Synthetic HDLs with a nanocrystal core for imaging atherosclerotic plaque Representations of the three nanocrystal HDLs Synthesis of the nanocrystal HDLs Luthi AJ, et al. Trends Mol Med. 2010, 16,

49 Infusion of rhdl Leads to Acute Changes in Human Atherosclerotic Plaque rhdl 80 mg/kg, iv Shaw, JA, et al. Circ Res. 2008;103;

50 Effect of rhdl infusion on metabolic parameters in type 2 diabetes mellitus Drew BC, et al. Circulation. 2009;119:

51 Effect of rhdl infusion on inflammation and cholesterol efflux in type 2 diabetes mellitus Sanjay Patel S, et al. JACC 2009; 53:962 71

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53 H μοριακή βάση της διαβητικής δυσλιπιδαιμίας στους ασθενείς με σακχαρώδη διαβήτη τύπου 2 Mazzone Th, et al. Lancet 2008; 371: