Mabley Jon G, Horváth Eszter M, Murthy Kanneganti G K, Zsengellér Zsuzsanna, Vaslin Anne, Benko Rita, Kollai Márk, Szabó Csaba
Inotek Pharmaceuticals Corporation, Beverly, Massachusetts, USA.
J Pharmacol Exp Ther. 2005 Nov;315(2):812-20. doi: 10.1124/jpet.105.090480. Epub 2005 Aug 3.
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-alpha and macrophage inflammatory protein-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. 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-beta-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 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 by PARP in male animals.
聚（ADP - 核糖）聚合酶（PARP）的激活是多种心血管疾病和炎症性疾病发病机制中的一个重要因素。在此，我们报告PARP在雄性动物中优先下调性别特异性炎症反应。雌性小鼠对内毒素诱导的全身炎症反应产生的肿瘤坏死因子 - α和巨噬细胞炎性蛋白 - 1α比雄性小鼠少，并且对内毒素诱导的死亡具有抗性。PARP的药理学抑制在降低雄性小鼠而非雌性小鼠的炎症介质产生和死亡率方面有效。卵巢切除术部分逆转了雌性小鼠中观察到的保护作用。如流式细胞术所示，药理学PARP抑制可降低雄性动物而非雌性动物循环白细胞中内毒素诱导的PARP激活。用17 - β - 雌二醇预处理雄性小鼠可预防内毒素诱导的肝损伤并降低体内的聚（ADP - 核糖基）化。在内毒素诱导内皮依赖性舒张反应受损的动物中，PARP抑制可预防这种损伤，这种情况在雄性动物而非雌性动物中出现。与雄性血清相比，置于雌性大鼠血清中的培养细胞中，体外氧化剂诱导的PARP激活减少。雌激素在体外不直接抑制PARP的酶活性。然而，PARP和雌激素受体α形成复合物，该复合物在体外与DNA结合，并且雌激素可增强该复合物与DNA的结合。因此，雌激素可能将PARP锚定到雌激素受体α和DNA上，阻止其识别DNA链断裂并因此阻止其激活。总之，炎症反应中的性别差异显示PARP在雄性动物中优先发挥调节作用。
