Abstract
Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here, we report that the gender-specific inflammatory response is preferentially down-regulated by PARP in male animals. Female mice produce less tumor necrosis factor-α and macrophage inflammatory protein-1α in response to systemic inflammation induced by endotoxin than male mice and are resistant to endotoxin-induced mortality. Pharmacological inhibition of PARP is effective in reducing inflammatory mediator production and mortality in male, but not in female, mice. Ovariectomy partially reverses the protection seen in female mice. Endotoxin-induced PARP activation in circulating leukocytes is reduced in male, but not female, animals by pharmacological PARP inhibition, as shown by flow cytometry. Pretreatment of male mice with 17-β-estradiol prevents endotoxin-induced hepatic injury and reduces poly(ADP-ribosyl)ation in vivo. In male, but not female, animals, endotoxin induces an impairment of the endothelium-dependent relaxant responses, which is prevented by PARP inhibition. In vitro oxidant-induced PARP activation is reduced in cultured cells placed in female rat serum compared with male serum. Estrogen does not directly inhibit the enzymatic activity of PARP in vitro. However, PARP and estrogen receptor α form a complex, which binds to DNA in vitro, and the DNA binding of this complex is enhanced by estrogen. Thus, estrogen may anchor PARP to estrogen receptor α and to the DNA and prevent its recognition of DNA strand breaks and hence its activation. In conclusion, the gender difference in the inflammatory response shows preferential modulation by PARP in male animals.
Footnotes
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This work was supported by Grant R01 HL59266 from the National Institutes of Health and by Grant AT049488 from the Hungarian Research Fund (Országos Tudományos Kutatási Alapprogramok). E.M.H. was supported by the Hungarian National Eötvös Fellowship.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.090480.
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ABBREVIATIONS: PARP, poly(ADP-ribose) polymerase; TNF, tumor necrosis factor; LPS, lipopolysaccharide; MIP, macrophage inflammatory protein; PJ34, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethyl-acetamide HCl; INO-1001, indeno[1,2-c]isoquinolinone-based PARP inhibitor; PAR, poly(ADP-ribose); R1, region 1; ER, estrogen receptor; PBS, phosphate-buffered saline; EMSA, electrophoretic mobility shift assay; ED, estrogen.
- Received June 14, 2005.
- Accepted August 1, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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