Received for publication June 14, 2005.
Revised July 28, 2005.
Accepted for publication August 1, 2005.

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

Abstract

Activation of poly(ADP-ribose) polymerase is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here we report that the gender-specific inflammatory response is preferentially regulated by PARP in male animals. Female mice produce less tumor-necrosis factor-alpha (TNF-alpha and MIP-1alpha) 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. Ovarectomy partially reverses the protection seen in female mice. Endotoxin-induced PARP activation in circulating monocytes is inhibited in male, but not female animals by pharmacological PARP inhibition, as shown by flow cytometry. Pretreatment with 17-beta-estradiol (estrogen) 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, as compared to male serum. Estrogen doesn't directly inhibit the enzymatic activity of PARP in vitro. However, PARP and estrogen receptor alpha 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 alpha 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 in male animals by PARP inhibition.

Key words: apopotosis, endotoxin, inflammation, necrosis, shock, vascular

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