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PMID: 9520459 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 7 ·1998-03-31 ·Pages 3867-72

Szabó C, Virág L, Cuzzocrea S, Scott GS, Hake P, O'Connor MP, Zingarelli B, Salzman A, Kun E

Abstract

Peroxynitrite, a cytotoxic oxidant formed from nitric oxide (NO) and superoxide, induces DNA strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthase (PARS; EC 2.4.2.30). The cellular function of PARS was determined in fibroblast lines from PARS knockout animals (PARS-/-) and corresponding wild-type animals (PARS+/+), with the aid of the lipophilic PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP). We investigated the role of PARS in peroxynitrite-induced fibroblast injury in vitro and also in the development of arthritis in vivo. Exposure of embryonic fibroblasts from the PARS+/+ animals to peroxynitrite caused DNA single-stand breakage and PARS activation and caused an acute suppression of mitochondrial respiration. INH2BP protected the PARS+/+ cells against the suppression of mitochondrial respiration in response to peroxynitrite (50-100 microM). Similarly to PARS inhibition with INH2BP, the PARS-/- cells were protected against peroxynitrite-induced injury. The protection against cellular injury by PARS-/- phenotype or INH2BP waned when cells were challenged with higher concentrations of the oxidant. Inhibition of PARS by INH2BP or by PARS-/- phenotype reduced inducible nitric-oxide synthase (iNOS; EC 1.14.13.39) mRNA levels and inhibited production of NO in immunostimulated cells. INH2BP had no peroxynitrite scavenging or hydroxyl radical scavenging effects, and it exerted no additional (nonspecific) effects in the PARS-/- cells. In collagen-induced arthritis, significant staining for nitrotyrosine, a marker of peroxynitrite formation, was found in the inflamed joints. Oral treatment with INH2BP (0.5 g/kg, daily), starting at the onset of arthritis (day 25), delayed the development of the clinical signs at days 26-35 and improved histological status in the knee and paw. Our data demonstrate that deletion of PARS by genetic manipulation or pharmacological inhibition of PARS protects against oxidant-induced cellular injury in vitro and exhibits anti-inflammatory effects in vivo.

MeSH Terms
Animals Arthritis/chemically induced,pathology,prevention & control Coumarins/pharmacology,therapeutic use DNA Damage/drug effects Enzyme Inhibitors/pharmacology,therapeutic use Fibroblasts/drug effects,pathology Mice Nitrates/toxicity Oxidants/toxicity Poly(ADP-ribose) Polymerase Inhibitors
Chemicals
Coumarins Enzyme Inhibitors Nitrates Oxidants Poly(ADP-ribose) Polymerase Inhibitors 5-iodo-6-amino-1,2-benzopyrone peroxynitric acid
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Szabó C
Division of Critical Care, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. csaba.szabo@chmcc.org
Virág L
Cuzzocrea S
Scott G S
Hake P
O'Connor M P
Zingarelli B
Salzman A
Kun E
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.7.3867
Email
csaba.szabo@chmcc.org
Published
1998-03-31
Pages
3867-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC19929
Subset
IM
Grants
NIGMS NIH HHS · R29GM54773 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.7.3867 PMC Full Text View journal details
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