Angiotensin II-mediated endothelial dysfunction: Role of poly(ADP-ribose) polymerase activation

Csaba Szabo, Pál Pacher, Zsuzsanna Zsengellér, Anne Vaslin, Katalin Komjáti, Rita Benkö, Min Chen, Jon G. Mabley, Márk Kollai

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors P J34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AII-induced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalMolecular Medicine
Volume10
Issue number1-6
StatePublished - Jan 2004
Externally publishedYes

Fingerprint

Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Angiotensin II
Poly Adenosine Diphosphate Ribose
Reactive Nitrogen Species
Angiotensin Receptors
Enalapril
Enzyme Activation
Losartan
DNA
Vascular Endothelium
Inbred SHR Rats
NADP
Angiotensin-Converting Enzyme Inhibitors
Oxidants
Nitric Oxide Synthase
Aorta
Cultured Cells
Reactive Oxygen Species
Oxidoreductases

ASJC Scopus subject areas

  • Genetics

Cite this

Szabo, C., Pacher, P., Zsengellér, Z., Vaslin, A., Komjáti, K., Benkö, R., ... Kollai, M. (2004). Angiotensin II-mediated endothelial dysfunction: Role of poly(ADP-ribose) polymerase activation. Molecular Medicine, 10(1-6), 28-35.

Angiotensin II-mediated endothelial dysfunction : Role of poly(ADP-ribose) polymerase activation. / Szabo, Csaba; Pacher, Pál; Zsengellér, Zsuzsanna; Vaslin, Anne; Komjáti, Katalin; Benkö, Rita; Chen, Min; Mabley, Jon G.; Kollai, Márk.

In: Molecular Medicine, Vol. 10, No. 1-6, 01.2004, p. 28-35.

Research output: Contribution to journalArticle

Szabo, C, Pacher, P, Zsengellér, Z, Vaslin, A, Komjáti, K, Benkö, R, Chen, M, Mabley, JG & Kollai, M 2004, 'Angiotensin II-mediated endothelial dysfunction: Role of poly(ADP-ribose) polymerase activation', Molecular Medicine, vol. 10, no. 1-6, pp. 28-35.
Szabo C, Pacher P, Zsengellér Z, Vaslin A, Komjáti K, Benkö R et al. Angiotensin II-mediated endothelial dysfunction: Role of poly(ADP-ribose) polymerase activation. Molecular Medicine. 2004 Jan;10(1-6):28-35.
Szabo, Csaba ; Pacher, Pál ; Zsengellér, Zsuzsanna ; Vaslin, Anne ; Komjáti, Katalin ; Benkö, Rita ; Chen, Min ; Mabley, Jon G. ; Kollai, Márk. / Angiotensin II-mediated endothelial dysfunction : Role of poly(ADP-ribose) polymerase activation. In: Molecular Medicine. 2004 ; Vol. 10, No. 1-6. pp. 28-35.
@article{fd8e5012e56a43edb24f2e5e45ad4e15,
title = "Angiotensin II-mediated endothelial dysfunction: Role of poly(ADP-ribose) polymerase activation",
abstract = "Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors P J34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AII-induced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension.",
author = "Csaba Szabo and P{\'a}l Pacher and Zsuzsanna Zsengell{\'e}r and Anne Vaslin and Katalin Komj{\'a}ti and Rita Benk{\"o} and Min Chen and Mabley, {Jon G.} and M{\'a}rk Kollai",
year = "2004",
month = "1",
language = "English (US)",
volume = "10",
pages = "28--35",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",
number = "1-6",

}

TY - JOUR

T1 - Angiotensin II-mediated endothelial dysfunction

T2 - Role of poly(ADP-ribose) polymerase activation

AU - Szabo, Csaba

AU - Pacher, Pál

AU - Zsengellér, Zsuzsanna

AU - Vaslin, Anne

AU - Komjáti, Katalin

AU - Benkö, Rita

AU - Chen, Min

AU - Mabley, Jon G.

AU - Kollai, Márk

PY - 2004/1

Y1 - 2004/1

N2 - Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors P J34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AII-induced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension.

AB - Angiotensin II (AII) contributes to the pathogenesis of many cardiovascular disorders. Oxidant-mediated activation of poly(adenosine diphosphate-ribose) polymerase (PARP) plays a role in the development of endothelial dysfunction and the pathogenesis of various cardiovascular diseases. We have investigated whether activation of the nuclear enzyme PARP contributes to the development of AII-induced endothelial dysfunction. AII in cultured endothelial cells induced DNA single-strand breakage and dose-dependently activated PARP, which was inhibited by the AII subtype 1 receptor antagonist, losartan; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin; and the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester. Infusion of sub-pressor doses of AII to rats for 7 to 14 d induced the development of endothelial dysfunction ex vivo. The PARP inhibitors P J34 or INO-1001 prevented the development of the endothelial dysfunction and restored normal endothelial function. Similarly, PARP-deficient mice infused with AII for 7 d were found resistant to the AII-induced development of endothelial dysfunction, as opposed to the wild-type controls. In spontaneously hypertensive rats there was marked PARP activation in the aorta, heart, and kidney. The endothelial dysfunction, the cardiovascular alterations and the activation of PARP were prevented by the angiotensin-converting enzyme inhibitor enalapril. We conclude that AII, via AII receptor subtype 1 activation and reactive oxygen and nitrogen species generation, triggers DNA breakage, which activates PARP in the vascular endothelium, leading to the development of endothelial dysfunction in hypertension.

UR - http://www.scopus.com/inward/record.url?scp=7444234222&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7444234222&partnerID=8YFLogxK

M3 - Article

C2 - 15502880

AN - SCOPUS:7444234222

VL - 10

SP - 28

EP - 35

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

IS - 1-6

ER -