Peroxynitrite modulates MnSOD gene expression in lung epithelial cells

Robert M. Jackson, Gregory Parish, Eric S. Helton

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Peroxynitrite (ONOO-) is a strong oxidant derived from nitric oxide (·NO) and superoxide (O2(·-)), reactive nitrogen (RNS) and oxygen species (ROS) present in inflamed tissue. Other oxidant stresses, e.g., TNF-α and hyperoxia, induce mitochondrial, manganese-containing superoxide dismutase (MnSOD) gene expression. These experiments tested whether ONOO- regulated MnSOD gene expression in human lung epithelial (A549) cells. 3- morpholinosydnonimine HCl (SIN-1) (10 or 1000 μM) increased MnSOD mRNA, but did not change hypoxanthine guanine phosphoribosyl transferase (HPRT) mRNA. Authentic peroxynitrite (ONOO-) (100-500 μM) also increased MnSOD mRNA but did not change constitutive HPRT mRNA expression. ONOO- stimulated luciferase gene expression driven by a 2.5 kb fragment of the rat MnSOD gene 5' promoter region. MnSOD gene induction due to ONOO- was inhibited effectively by L-cysteine (10 mM) and partially inhibited by N-acetyl cysteine (50 mM) or pyrrole dithiocarbamate (10 mM). ·NO from 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA NONOate) (100 or 1000 μM) did not change MnSOD or HPRT mRNA. Neither H2O2 nor NO2-, breakdown products of SIN-1 and ONOO-, had any effect on MnSOD mRNA expression; however, ONOO- and SIN-1 did not increase MnSOD protein content detectable by western blots, nor did they increase MnSOD enzymatic activity. Increased steady state [O2(·-)] in the presence of ·NO yields ONOO-, and ONOO- has direct, stimulatory effects on MnSOD transcript expression.

Original languageEnglish (US)
Pages (from-to)463-472
Number of pages10
JournalFree Radical Biology and Medicine
Volume25
Issue number4-5
DOIs
StatePublished - Sep 1 1998
Externally publishedYes

Keywords

  • Epithelial cells
  • Nitric oxide
  • Peroxynitrite
  • Superoxide dismutase

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

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