Μηχανισµός της απώλειας της καρδιοπροστατευτικής δράσης της µετισχαιµικής προστασίας (postconditioning) στην αθηρωµάτωση Iωάννα Ανδρεάδου

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Norman Hill
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1 Μηχανισµός της απώλειας της καρδιοπροστατευτικής δράσης της µετισχαιµικής προστασίας (postconditioning) στην αθηρωµάτωση Iωάννα Ανδρεάδου School of Pharmacy, University of Athens, Greece

2 Definitions Preconditioning: Repeated brief episodes of ischemia-reperfusion applied before a subsequent prolonged ischemic insult (1986) 1h appr h Postconditioning: Repeated brief episodes of ischemia-reperfusion applied at the onset of reperfusion following a previous prolonged (2003) ischemic insult

3 Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention Xavier Freixa*,et al., European Heart Journal (2012) 33, The use of pharmacological agents to emulate p-cond effects without requiring a mechanical intervention poses another alternative that would avoid the potential risk of embolization and allow a non-restricted aspiration sequence. Further studies will be required to know whether pharmacological strategies could have the same effect as mechanical p-conditioning trials. Reduction of infarct size by ischaemic post-conditioning in humans: fact or fiction? Gerd Heusch, European Heart Journal (2012) 33, In my view, the mechanical procedure of ischaemic post-conditioning may indeed not become broadly applicable to recruit protection in clinical routine. However, the recognition of its potential and a better understanding of its underlying signal transduction may provide an important paradigm for cardioprotection and its translation to clinical use of pharmacological interventions.

4 PRECONDITIONING POSTCONDITIONING PRECONDITIONING, DELAYED PRECONDITIONING ΚΑΙ POSTCONDITIONING Gerd Heusch, et al Circulation, 2008, 118:

5 Reduction of infarct size by ischaemic post-conditioning in humans: fact or fiction? Gerd Heusch, European Heart Journal (2012) 33, 13 15

6 Comorbidities Diabetes Hypertrophy Ageing Hypercholesterolemia Increased Threshold Tsang A et al. Diabetes 2005;54: Leptin deficient mice with obesity, diabetes and hypercholesterolemia are not protected by PostC Bouhidel et al, Am J Physiol 2008;295:H J Am Coll Cardiol 2001;38:

7 Atherosclerosis 2006;188: Normal - Pathological

8 Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines Jing-Lin Zhao, Yue-Jin Yang, Shi-Jie You, Chuan-Jue Cui, Run-Lin Gao Microvascular Research 73 (2007) Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite. Kupai K, Csonka C, Fekete V, Odendaal L, van Rooven J, Marais de W, Csont T, Ferdinandy P. Am J Physiol Heart Circ Physiol Nov;297(5):H

9 The mechanisms by which hyperlipidemia may blunt the cardioprotective effects of ischemic conditioning are not clear. Hypercholesterolemia impairs endothelial function reduces NO synthesis, potentially by increasing the production of several oxidants such as peroxynitrite and lipid peroxidation compounds. The expression and activity of endothelial nitric oxide synthase (enos) synthesis may play a key role. Claudio Napoli, Filomena de Nigris, Sharon Williams-Ignarro, Orlando Pignalosa, Vincenzo Sica, Louis J. Ignar... Nitric oxide and atherosclerosis: An update Nitric Oxide Volume 15, Issue

10 Claudio Napoli, Filomena de Nigris, Sharon Williams-Ignarro, Orlando Pignalosa, Vincenzo Sica, Louis J. Ignar... Nitric oxide and atherosclerosis: An update Nitric Oxide Volume 15, Issue

11 Nitric Oxide and Peroxynitrite in Health and Disease PA L PACHER, JOSEPH S. BECKMAN, AND LUCAS LIAUDET Physiol Rev 87: , 2007;

13 HYPERCHOLESTEROLEMIA PROMOTES INFLAMMATION AND MICROVASCULAR DYSFUNCTION: ROLE OF NITRIC OXIDE AND SUPEROXIDE KAREN Y. STOKES, DIANNE COOPER, ANITABEN TAILOR, and D. NEIL GRANGER Free Radical Biology & Medicine, Vol. 33, No. 8, pp , 2002

15 Atherosclerosis 195 (2007) e210 e215 Effects of Levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure John T. Parissis, Ioanna Andreadou, Sophia L. Markantonis, Vasiliki Bistola, Asimina Louka, Anastasia Pyriochou, Ioannis Paraskevaidis, Gerasimos Filippatos, Efstathios K. Iliodromitis, Dimitrios Th. Kremastinos Circulation 2008, 117: : Inhibition of Interleukin-1 by Anakinra Improves Vascular and Left Ventricular Function in Patients With Rheumatoid Arthritis Ignatios Ikonomidis, John P. Lekakis, Maria Nikolaou, Ioannis Paraskevaidis, Ioanna Andreadou, Theophania Kaplanoglou, Pelagia Katsimbri, Grigorios Skarantavos, Panayiotis N. Soucacos and Dimitrios T. Kremastinos

16 If we increase the reduced bioavailability of NO is it possible to restore the infarct size limiting effect induced by PostC in hypercholesterolemia??

18 MDA µm/mg protein * * * * * Ischemic Control Sim POC Sim-POC Chol Chol-Sim Chol-POC Chol-Sim- POC 10 th min of reperfusion Control Sim NT nm/mg protein * * * * Ischemic * POC Sim-POC Chol Chol-Sim Chol-POC Chol-Sim- POC

19 Cholesterol mg/dl * * Control Sim Chol Chol-Sim Chol-POC Chol-Sim-POC Control 600 Sim LDL mg/dl * * POC Sim-POC Chol Chol-Sim Chol-POC Chol-Sim- POC

20 Is it possible if there is still hypercholesterolemia If we increase the reduced bioavailability of NO to restore the infarct size limiting effect induced by PostC in hypercholesterolemia?? Sata M.et al. The FASEB Journal 2001

21 Andreadou Ι.*, et al., Cardiovasc Res, 94: , 2012.

crucial mechanism in direct cardioprotection.

23 It seems that the attenuation of nitro-oxidative stress at reperfusion, although it may partly restore NO biovailability in hypercholesteromia, may not be a crucial mechanism in direct cardioprotection. Thus, the latter may be related to the varying degrees of activation or phosphorylation of the intracellular mediators.

$related to the high 45% unbound fraction of pravastatin sodium in plasma, which may interact actively with the endothelium and activate the enos/akt signalling$

25 It seems that pravastatin unlike simvastatin and the other statins has the potential to interact with the endothelium with a unique manner This may partly be related to the high 45% unbound fraction of pravastatin sodium in plasma, which may interact actively with the endothelium and activate the enos/akt signalling cascade.

26 J Am Coll Cardiol Jan;33(1): Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW. We determined PRA and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cel Both PRA and SIM activate enos, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on enos activation.

27 CONCLUSIONS 1. PostC reduce final infarct size under normal conditions, but its infarct size limiting effect is blunted in hypercholesterolemia and atheromatosis. 2. The increase of the reduced bioavailability of NO may restore PostC s infarct size limiting effect in hypercholesterolemia. 3. Pravastatin in contrast to simvastatin, reduces infarct size and restores postconditioning-conferred cardiorpotection in hypercholesterolemic rabbits independently of lipid lowering, potentially through Akt/eNOs activation and greater nitrooxidative stress attenuation.

28 School of Pharmacy, University of Athens Sophia-Iris Bibli BPharm Katerina Spyridaki BPharm Anastasia Zoga PhD Eftyhios Prokovas MD Medical School, University of Athens Efstathios Iliodromitis MD, PhD Dimitrios Kremastinos MD, PhD

Received 10 November 2011; revised 29 February 2012; accepted 8 March 2012; online publish-ahead-of-print 12 March 2012

Received 10 November 2011; revised 29 February 2012; accepted 8 March 2012; online publish-ahead-of-print 12 March 2012 Cardiovascular Research (2012) 94, 501 509 doi:10.1093/cvr/cvs121 Short-term statin administration in hypercholesterolaemic rabbits resistant to postconditioning: effects on infarct size, endothelial nitric