Gender differences in the endotoxin-induced inflammatory and vascular responses: Potential role of poly(ADP-ribose) polymerase activation

Jon G. Mabley, Eszter M. Horváth, Kanneganti G.K. Murthy, Zsuzsanna Zsengellér, Anne Vaslin, Rita Benko, Márk Kollai, Csaba Szabó

    Research output: Contribution to journalArticle

    82 Scopus citations

    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(ADPribosyl) 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.

    Original languageEnglish (US)
    Pages (from-to)812-820
    Number of pages9
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume315
    Issue number2
    DOIs
    StatePublished - Nov 2005

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

    Fingerprint Dive into the research topics of 'Gender differences in the endotoxin-induced inflammatory and vascular responses: Potential role of poly(ADP-ribose) polymerase activation'. Together they form a unique fingerprint.

  • Cite this