Új célmolekulák azonosítása a magas vérnyomás keltette vaszkuláris remodeling kivédésér
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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

Sümegi Balázs

Pécsi Tudományegyetem

Általános Orvostudományi Kar

Biokémiai és Orvosi Kémiai Intézet

és Szentágothai János Kutató Központ


Hypertension is a major public health problem keltette vaszkuláris remodeling kivédésér

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 contributing keltette vaszkuláris remodeling kivédésérto 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.


Most of the direct antioxidant have low efficacy keltette vaszkuláris remodeling kivédésér

to prevent oxidative stress

British Journal of Pharmacology (2009), 157, 935–943.


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.


Abnormal ROS metabolism and its consequences diseases

in the vascular system

Inflammation

Cell Death

Abnormal signaling

inducing remodeling


Why PARP inhibitors have the potential to prevent diseases

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.


Designing PARP inhibitors: diseasesCollaboration with Hideg K& Kalai T group

Carboxaminobenzimidazol- 4-hydroxyquinazolin +Antioxidant groups


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


* rats

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



Dose - response i ratssometric 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


Arterial stiffness index of aorta of normotensive rats

(WKY-C, WKY-L) and hypertensive (SHR-C, SHR-L) rats

Values are mean ±SEM


A rats

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


Effect of PARP inhibitor ratson oxidative stress


A rats

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.


Effect of PARP inhibitor ratson signaling


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


Representative merged confocal images of Akt 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


Effect of PARP-1 on MAP kinases in Akt

vascular remodeling

Hypertension

ROS

DNAbreaks

PARP-1

inhibitor

ASK1

PARP-1

activation

p38

JNK

MKP1

Expression



Transcription factors activation in hypertension Akt

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.


Regulation of Crm1-dependent nuclear export by PARP-1 Akt

Crm1 (Exporting1) export proteins from the nucleus to cytoplasm


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.


Effect of Oxidative stress and PARP inhibitor on the PARP-1

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.


Poly-ADP-ribosylation is a genome wide regulator of PARP-1

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


Participants: PARP-1

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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