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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 kivédésére
Általános Orvostudományi Kar
Biokémiai és Orvosi Kémiai Intézet
és Szentágothai János Kutató Központ
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
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.
to prevent oxidative stress
British Journal of Pharmacology (2009), 157, 935–943.
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!
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.
Angiotensin II receptor blockers! Difficult to separate blood pressure lowering effect and protective effects.
Raising the protective role of PARP inhibitor which can modulates signaling,
transcription factors activity, stabilize mitochondrial membrane system
and protect against cell death.
in the vascular system
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.
Carboxaminobenzimidazol- 4-hydroxyquinazolin +Antioxidant groups
Chemical structure of L-2286 (2-[(2-Piperidine-1-ylethyl)thio]
Kaplan–Meier survival curves
of SHR-C and SHR-L groups
46 weeks treatment, 5 mg/kg/day
Systolic blood pressure values of normotensive (WKY-C, WKY-L)
and hypertensive (SHR-C, SHR-L) rats. Values are means ±SEM
Dose - response isometric vasomotor responses of (WKY, SHR-C, SHR-L) rat carotid arteriesto acetyl-choline
All values are normalized toKCl (60mM) responses (100%)
Values are mean ±SEM
(WKY-C, WKY-L) and hypertensive (SHR-C, SHR-L) rats
Values are mean ±SEM
Representative histologic sections
stained with Masson’s trichrome (n= 4)
Magnifications 40x fold. Aorta
(B)Wistard + L-2286,
(C) SHR rats,
(D) SHR rats + L-2286
Effect of PARP inhibition on thedeposition of interstitial collagenin rat aorta
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.
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
Ser473 (60 kDa)
Thr183-Tyr185 (46-54 kDa)
Thr183-Tyr185 (42,44 kDa)
Thr180-Gly-Tyr182 (43 kDa)
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
TGF-1 – Smad
Oxidative stress driven beta-catenin nuclear translocation
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.
Crm1 (Exporting1) export proteins from the nucleus to cytoplasm
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.
activation of transcription factors(TransAM kit)
ATF2 (activating transcription factor 2)
Signal transducer and activator
of transcription (Stat)
Myocyte enhancer factor-2 (MEF2)
Curr Opin Cell Biol. 2008 20, 294-302.Transcriptional control by PARP-1:
chromatin modulation, enhancer-binding, co-regulation, and insulation. Kraus WL.
gene expression in vascular remodeling
Racz et al. Regulation of MKP-1 expression
by PARP-1. Free Radic Biol Med. (2010)
c-Jun, ATF2, LEK1, SMAD4
p53, NFAT1,4, STAT4, TDF/MEF2
p53, NFB, Creb,
ATF, Chop, MSK
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
Organic and Pharmacological Chemistry
Kálmán Hideg, Tamás Kálai
Department of Pathophysiology and Gerontology
Ákos Koller, Zoltán Vámos