Inhibition of terminal calcium overload protects against peroxynitrite- induced cellular injury in macrophages

Csaba Szabo, Andrew L. Salzman

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The inducible isoform of nitric oxide synthase (iNOS) produces large quantities of nitric oxide (NO) during inflammation and shock. Recent studies show that the reaction of NO with superoxide yields the cytotoxic oxidant peroxynitrite (ONOO-). An important pathway of ONOO- cytotoxicity involves DNA strand breakage, activation of the nuclear repair enzyme poly(ADP) ribosyltransferase (PARS), and concomitant ADP-ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Using quin-2, a calcium chelator, we have investigated the role of calcium in the cytotoxicity elicited by ONOO-. Quin-2 (10-100 μM) ameliorated the suppression of mitochondrial respiration in response to ONOO- (1 mM) in J774 macrophages. Quin-2 at 100 μM, but not at 10 μM, caused a small (20%) inhibition of PARS activity, and did not significantly affect NAD+ depletion. Quin-2 exhibited a slight protective effect against the decrease in mitochondrial respiration in immunostimulated macrophages which endogenously produce ONOO-. These results suggest that the protective effect of quin-2 against the ONOO--induced cellular injury is not due to interference with PARS activation or NAD+ depletion, but rather due to interference with a delayed intracellular event, possibly terminal calcium overload due to inhibition of mitochondrial enzymes and membrane pumps. Inhibition of calcium overload may be a viable experimental strategy to limit ONOO- cytotoxicity.

Original languageEnglish (US)
Pages (from-to)163-167
Number of pages5
JournalImmunology Letters
Volume51
Issue number3
DOIs
StatePublished - Jul 1996
Externally publishedYes

Fingerprint

Peroxynitrous Acid
ADP Ribose Transferases
Macrophages
Calcium
NAD
Wounds and Injuries
Nitric Oxide
Respiration
Mitochondrial Membranes
Nitric Oxide Synthase Type II
Enzymes
Oxidants
Superoxides
Adenosine Diphosphate
Shock
Protein Isoforms
Quin2
Inflammation
DNA

Keywords

  • Calcium
  • Endotoxin
  • Hydroxyl radical
  • Inflammation
  • Mitochondrial respiration
  • Nitric oxide
  • Nitric oxide synthase
  • Peroxynitrite
  • Poly ADP-ribosyl synthetase
  • Quin- 2
  • Shock
  • Superoxide

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Inhibition of terminal calcium overload protects against peroxynitrite- induced cellular injury in macrophages. / Szabo, Csaba; Salzman, Andrew L.

In: Immunology Letters, Vol. 51, No. 3, 07.1996, p. 163-167.

Research output: Contribution to journalArticle

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abstract = "The inducible isoform of nitric oxide synthase (iNOS) produces large quantities of nitric oxide (NO) during inflammation and shock. Recent studies show that the reaction of NO with superoxide yields the cytotoxic oxidant peroxynitrite (ONOO-). An important pathway of ONOO- cytotoxicity involves DNA strand breakage, activation of the nuclear repair enzyme poly(ADP) ribosyltransferase (PARS), and concomitant ADP-ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Using quin-2, a calcium chelator, we have investigated the role of calcium in the cytotoxicity elicited by ONOO-. Quin-2 (10-100 μM) ameliorated the suppression of mitochondrial respiration in response to ONOO- (1 mM) in J774 macrophages. Quin-2 at 100 μM, but not at 10 μM, caused a small (20{\%}) inhibition of PARS activity, and did not significantly affect NAD+ depletion. Quin-2 exhibited a slight protective effect against the decrease in mitochondrial respiration in immunostimulated macrophages which endogenously produce ONOO-. These results suggest that the protective effect of quin-2 against the ONOO--induced cellular injury is not due to interference with PARS activation or NAD+ depletion, but rather due to interference with a delayed intracellular event, possibly terminal calcium overload due to inhibition of mitochondrial enzymes and membrane pumps. Inhibition of calcium overload may be a viable experimental strategy to limit ONOO- cytotoxicity.",
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