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Új célmolekulák azonosítása a magas vérnyomás keltette vaszkuláris remodeling kivédésér e

Új célmolekulák azonosítása a magas vérnyomás keltette vaszkuláris remodeling kivédésér e. Sümegi Balázs. Pécsi Tudományegyetem Általános Orvostudományi Kar Biokémiai és Orvosi Kémiai Intézet és Szentágothai János Kutató Központ. Hypertension is a major public health problem. .

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Új célmolekulák azonosítása a magas vérnyomás keltette vaszkuláris remodeling kivédésér e

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  1. Új célmolekulák azonosítása a magas vérnyomás keltette vaszkuláris remodeling kivédésére Sümegi Balázs Pécsi Tudományegyetem Általános Orvostudományi Kar Biokémiai és Orvosi Kémiai Intézet és Szentágothai János Kutató Központ

  2. Hypertension is a major public health problem  Hypertension is a complex disease and an important risk factor for cardiovascular outcomes, such as sudden death, myocardial infarction, heart failure, and renal diseases and stroke  The control of arterial hypertension is far from optimal  Side effects of antihypertensive drugs  Low blood pressure may lead to cognitive impairment in the elderly population

  3. Redox-dependent mechanisms contributingto vascular remodeling in hypertension All cell types of the vessel wall produce reactive oxygen species (ROS). Vascularsmooth muscle cells VSMC: endothelial cells (EC); Macrophages (Mϕ); T-cells whichinduces increased vascular ROS production and leads to VSMC growth (proliferationand hypertrophy), increased vasoconstriction, endothelial dysfunction, inflammation.

  4. Most of the direct antioxidant have low efficacy to prevent oxidative stress British Journal of Pharmacology (2009), 157, 935–943.

  5. ROS is a significant factor in the pathogenesis of vascular diseases 1. Scavangering ROS can be an attractive therapy? Antioxidant drugs (for example, vitamins C and E, and β-carotene) do not appear to have the clinical efficacy to prevent cardiovascular events! What are the reasons? Antioxidant can be effective only in mM concentration range! 2. Targeting ROS production by blocking the activity of NADPH oxidases can be more effective? In knockout mice has some protection, but there are very few data with synthetic inhibitor and has to use high concentrations. 3. Angiotensin II receptor blockers! Difficult to separate blood pressure lowering effect and protective effects. 4. Raising the protective role of PARP inhibitor which can modulates signaling, transcription factors activity, stabilize mitochondrial membrane system and protect against cell death.

  6. Abnormal ROS metabolism and its consequences in the vascular system Inflammation Cell Death Abnormal signaling inducing remodeling

  7. Why PARP inhibitors have the potential to prevent hypertension induced vascular remodeling PARP inhibitor can inhibit oxidative stress induced cell damages, and prevents the induction of inflammation. Our previous data show that PARP inhibitor can prevent hypertension induced heart failure in a spontaneously hypertensive rat model .Cardiovasc Res. 2009; 83, 501-10. We have to keep in mind that only long chronic studies can serve as realistic model for human cases.

  8. Designing PARP inhibitors: Collaboration with Hideg K& Kalai T group Carboxaminobenzimidazol- 4-hydroxyquinazolin +Antioxidant groups

  9. PARP inhibitor significantly extended the life-span of SHR rats L-2286 Chemical structure of L-2286 (2-[(2-Piperidine-1-ylethyl)thio] quinazolin-4(3H)-one) PARP inhibitor Kaplan–Meier survival curves of SHR-C and SHR-L groups 46 weeks treatment, 5 mg/kg/day L-2286 PARP-inhibitor

  10. * Systolic blood pressure values of normotensive (WKY-C, WKY-L) and hypertensive (SHR-C, SHR-L) rats. Values are means ±SEM SHR SHR+PARPWKYWKY+PARP

  11. Effect of PARP inhibitor on the vascular functions and morphology

  12. Dose - response isometric vasomotor responses of (WKY, SHR-C, SHR-L) rat carotid arteriesto acetyl-choline A 10-9 10-8 10-7 10-6 10-5 All values are normalized toKCl (60mM) responses (100%) Values are mean ±SEM

  13. Arterial stiffness index of aorta of normotensive (WKY-C, WKY-L) and hypertensive (SHR-C, SHR-L) rats Values are mean ±SEM

  14. A B C D Representative histologic sections stained with Masson’s trichrome (n= 4) Magnifications 40x fold. Aorta (A)Wistard, (B)Wistard + L-2286, (C) SHR rats, (D) SHR rats + L-2286 Effect of PARP inhibition on thedeposition of interstitial collagenin rat aorta

  15. Effect of PARP inhibitor on oxidative stress

  16. A B C D Representative immunohistochemical stainings for nitrotyrosine formation (NT, brown staining) in the aortic wall of normotensive (WKY-C, WKY-L)and hypertensive (SHR-C, SHR-L) animals. Magnification 40 x fold. A: aortic wall of WKY-C, B: aortic wall of WKY-L, C: aortic wall of SHR-C,D: aortic wall of SHR-L.

  17. Effect of PARP inhibitoron signaling

  18. Effect of L-2286 treatment on the phosphorylation state of Akt-1, JNK, ERK and p38-MAPK in aortas normotensive (WKY-C, WKY-L) and hypertensive (SHR-C, SHR-L) rats WKY-C WKY-L SHR-C SHR-L Anti-PAR (116 kDa) p-Akt-1 Ser473 (60 kDa) JNK Thr183-Tyr185 (46-54 kDa) p-ERK 1/2 Thr183-Tyr185 (42,44 kDa) p-P38-MAPK Thr180-Gly-Tyr182 (43 kDa) ACTIN

  19. Representative merged confocal images of the localization of MKP-1. MKP-1 immunoreactivity (red) and Hoechst nuclear staining (blue) were presented inmerged form A: aortic wall of WKY-C B: aortic wall of WKY-L C: aortic wall of SHR-C D: aortic wall of SHR-L A B C D

  20. Effect of PARP-1 on MAP kinases in vascular remodeling Hypertension ROS DNAbreaks PARP-1 inhibitor ASK1 PARP-1 activation p38 JNK MKP1 Expression

  21. Genome wide effect of PARP inhibitors on transcription

  22. Transcription factors activation in hypertension NF-B AP-1 TGF-1 – Smad Oxidative stress driven beta-catenin nuclear translocation FOXO HIF-1 PARP inhibitor inactivates NF-Bby inhibiting 2 retrograde PAR dependent activation pathways and promoting the nuclear export of p65 component of NF-B PARP inhibitor inactivates AP-1 likely by preventing its activation by JNK which can be the consequence ofPARP-inhibition induced activation of Mkp-1 (MAP kinase phosphatase-1). Racz et al. Free Rad. Biol. Med. (2010) 49, 1978-88.

  23. Regulation of Crm1-dependent nuclear export by PARP-1 Crm1 (Exporting1) export proteins from the nucleus to cytoplasm

  24. Multiple modes of genome wide transcriptional regulation by PARP-1 A. PARP-1 can function as a transcriptional coregulator and corepressors. B. PARP-1 can act as an enhancer-binding factor (to protein or DNA) C. DNA-binding activators or repressors, or exchange factor. D. PARP-1 function as a component of insulators, which act to limit the effects of enhancers on promoters or by preventing the spread of heterochromatin. In this mode, the PARylation of CTCF by PARP-1 is likely to be important.

  25. Effect of Oxidative stress and PARP inhibitor on the activation of transcription factors(TransAM kit) P-c-Jun ATF2 (activating transcription factor 2) 2,5 2,5 2 2 ** 1,5 *** 1,5 p-c-Jun activation *** p-ATF2 activation 1 1 0,5 0,5 0 0 control PJ-34 H2O2 H2O2+PJ-34 control PJ-34 H2O2 H2O2+PJ-34 Signal transducer and activator of transcription (Stat) 2,85 Myocyte enhancer factor-2 (MEF2) 3 2,8 2,5 2,75 * 2 * STAT1- activation 2,7 MEF-2 activation 1,5 2,65 1 2,6 0,5 0 2,55 control PJ-34 H2O2 H2O2+PJ-34 control PJ-34 H2O2 H2O2+PJ-34 Curr Opin Cell Biol. 2008 20, 294-302.Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, co-regulation, and insulation. Kraus WL.

  26. Poly-ADP-ribosylation is a genome wide regulator of gene expression in vascular remodeling Hypertension Racz et al. Regulation of MKP-1 expression by PARP-1. Free Radic Biol Med. (2010) 49,1978-88. ROS DNAbreaks PARP-1 inh. ASK1 PARP-1 act. p38 JNK MKP1 act. c-Jun, ATF2, LEK1, SMAD4 p53, NFAT1,4, STAT4, TDF/MEF2 p53, NFB, Creb, ATF, Chop, MSK NFB Remodeling Remodeling

  27. Participants: Department of Biochemistry and Medical Chemistry Ferenc Gallyas Jr., Boglárka Rácz, Alíz Szabó 1st Department of Medicine Klára Magyar, László Deres, Krisztián Erős, Kitti Bruszt, Kálmán Tóth,Róbert Halmosi Central Electron Microscope Laboratory László Seress Organic and Pharmacological Chemistry Kálmán Hideg, Tamás Kálai Department of Pathophysiology and Gerontology Ákos Koller, Zoltán Vámos

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