Βιοδείκτες οξειδωτικού στρες

Transcript

1 ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΔΠΜΣ Ιατρική Χημεία Βιοδείκτες οξειδωτικού στρες Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχημείας Κλινικής Χημείας

2

3 Generation of superoxide ( O 2 ) and H 2 O 2 from O 2 in vascular cells Touyz RM, et al. Histochem Cell Biol (2004) 122:

4 Schematic diagram of the structure of the active NADPH oxidase complex Ray R, et al. Clinical Science (2005) 109,

5 Upstream regulators of NAD(P)H oxidase in vascular cells Touyz RM, et al. Histochem Cell Biol (2004) 122:

6 Interplay between NADPH oxidase and other sources of ROS Ray R, et al. Clinical Science (2005) 109,

7 Sources of ROS in vascular cells SOD Papaharalambus CA, et al. Trends Cardiovasc Med 2007;17:48 54

8 Functions of ROS in the immunological response against environmental pathogens Droge W, et al. Physiol Rev 82: 47 95, 2002

9 Regulation of the transcription factor hypoxia-inducible factor 1 (HIF-1) Droge W, et al. Physiol Rev 82: 47 95, 2002 Vascular remodeling Erythropoiesis Cell proliferation

10 Role of ROS in epidermal growth factor (EGF) receptor-mediated signaling Droge W, et al. Physiol Rev 82: 47 95, 2002

11 Role of ROS in insulin receptor kinase activation Droge W, et al. Physiol Rev 82: 47 95, 2002

12 Regulatory events and their dysregulation depend on the magnitude and duration of the change in ROS or reactive nitrogen species (RNS) concentration Catalase Glutathione peroxidase Thioredoxin Endoxenous antioxidants Droge W, et al. Physiol Rev 82: 47 95, 2002

13 ROS production in vascular injury Papaharalambus CA, et al. Trends Cardiovasc Med 2007;17:48 54

14 In situ detection of ROS and glutaredoxin in human coronary arteries ROS GRX

15 Endothelial Cells Macrophage Macrophage LDL oxldl

16 Συστατικά της OxLDL με προαθηρογόνο δράση Οξειδωμένη apob Οξειδωμένα φωσφολιπίδια Λυσο-φωσφατιδυλοχολίνη Οξειδωμένα παράγωγα λιπαρών οξέων (πχ ισοπροστάνια) Οξυστερόλες Αλδεϋδες Ολόκληρο το σωματίδιο της OxLDL

17 Ρόλος της OxLDL στην αθηροσκλήρωση

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

19 Colocalization of HOCl-modified epitopes with apoai or MPO is present on the endothelial layer as well as in the connective tissue Malle E, et al. Archives of Biochemistry and Biophysics 445 (2006)

20 Oxidative stress induces dysfunctional HDL HOCl-HDL Kontush A, et al. Pharmacol Rev 58: , 2006

21 Redox-dependent signaling pathways in vascular cells Touyz RM, et al. Histochem Cell Biol (2004) 122:

22 Role of ROS in the response to injury ROS mediate many of the responses to vascular injury Papaharalambus CA, et al. Trends Cardiovasc Med 2007;17:48 54

23 Vascular effects of ROS Touyz RM, et al. Histochem Cell Biol (2004) 122:

24 Oxidative phosphorylation, superoxide production, and scavenging pathways in Mitochondria Madamanchi NR, et al. Circ. Res. 2007;100;

25 Atherogenic mechanisms of mitochondrial dysfunction Madamanchi NR, et al. Circ. Res. 2007;100;

26 Insulin resistance and hyperglycemia-induced increased mitochondrial superoxide production activates atherogenic signaling pathways Madamanchi NR, et al. Circ. Res. 2007;100;

27 Biochemistry of oxidant stress biomarkers

28 Serum Levels of TBARS Predict Cardiovascular Events in Patients With Stable CAD (PREVENT Study) Walter MF, et al. J Am Coll Cardiol 2004;44:

29 8-isoprostanes Elevated plasma 8-isoprostane and reduced antioxidant capacity are associated with the extent and the severity of CAD Total Antioxidant Capacity Vassalle, et al. J Intern Med 2004; 256:

30

31 Assays for in-vivo detection of oxidative stress in uremia

32 Elevated plasma protein 3-chlorotyrosine a specific biomarker of MPO-catalyzed oxidation

33 Εffect of antioxidants on the risk of CAD

34 SPACE Trial profile HD ασθενείς με CAD 800 IU/day Lancet 2000; 356:

35 SPACE Trial Kaplan-Meier survival curves from primary cardiovascular-disease endpoints Lancet 2000; 356: 1213

36 Randomized Prospective Clinical Trials of Vitamin E in the Prevention of CAD Trial Vit E, IU/dl Subjects, n Follow-up, years Prevention Cardiovascular risk ATBC 50 29, Primary No effect GISSI 300 8, Secondary No effect HOPE 400 9, Secondary No effect CHAOS , Secondary Decrease, 47% SPACE Secondary Decrease, 54%

37 Summary of clinical trials for the effect of vitamin E supplementation in CAD

38 Strategies for the targeted delivery of antioxidants to mitochondria Sheu S-S, et al. Biochimica et Biophysica Acta 1762 (2006)