QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.090480v1 jpet.105.090480v2 315/2/812    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mabley, J. G. Articles by Szabó, C. Search for Related Content PubMed PubMed Citation Articles by Mabley, J. G. Articles by Szabó, C.

INFLAMMATION AND IMMUNOPHARMACOLOGY

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 Benk, Márk Kollai, and Csaba Szabó

Inotek Pharmaceuticals Corporation, Beverly, Massachusetts (J.G.M., E.M.H., K.G.K.M., Z.Z., A.V., R.B., C.S.); School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom (J.G.M.); Department of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Budapest, Hungary (E.M.H., R.B., M.K., C.S.); and Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, New Jersey (C.S.)

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- and macrophage inflammatory protein-1 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--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 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 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.

Address correspondence to: Dr. Csaba Szabó, Department of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Budapest, Ülli út 78/a, H-1082, Hungary. E-mail: szabocsaba{at}aol.com

This article has been cited by other articles:

				S. Matsubara, C. H. Swasey, J. E. Loader, A. Dakhama, A. Joetham, H. Ohnishi, A. Balhorn, N. Miyahara, K. Takeda, and E. W. Gelfand Estrogen Determines Sex Differences in Airway Responsiveness after Allergen Exposure Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 501 - 508. [Abstract] [Full Text] [PDF]

				S. Renolleau, S. Fau, and C. Charriaut-Marlangue Gender-Related Differences in Apoptotic Pathways After Neonatal Cerebral Ischemia Neuroscientist, February 1, 2008; 14(1): 46 - 52. [Abstract] [PDF]

				A. M. Hamby, S. W. Suh, T. M. Kauppinen, and R. A. Swanson Use of a Poly(ADP-Ribose) Polymerase Inhibitor to Suppress Inflammation and Neuronal Death After Cerebral Ischemia-Reperfusion Stroke, February 1, 2007; 38(2): 632 - 636. [Abstract] [Full Text] [PDF]