Pacher Pál, Cziráki Attila, Mabley Jon G, Liaudet Lucas, Papp Lajos, Szabó Csaba
Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA.
Biochem Pharmacol. 2002 Dec 15;64(12):1785-91. doi: 10.1016/s0006-2952(02)01421-1.
Reactive oxygen and nitrogen species are overproduced in the cardiovascular system during circulatory shock. Oxidant-induced cell injury involves the activation of poly(ADP-ribose) polymerase (PARP). Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the new potent phenanthridinone PARP inhibitor PJ34 [the hydrochloride salt of N-(oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide], we studied whether the impaired cardiac function in endotoxic shock is dependent upon the PARP pathway. Escherichia coli endotoxin (lipopolysaccharide, LPS) at 55 mg/kg, i.p., induced a severe depression of the systolic and diastolic contractile function, tachycardia, and a reduction in mean arterial blood pressure in both rats and mice. Treatment with PJ34 significantly improved cardiac function and increased the survival of rodents. In addition, LPS-induced depression of left ventricular performance was significantly less pronounced in PARP-1 knockout mice (PARP(-/-)) as compared with their wild-type littermates (PARP(+/+)). Thus, PARP activation in the cardiovascular system is an important contributory factor to the cardiac collapse and death associated with endotoxin shock.
在循环性休克期间，心血管系统中活性氧和氮物质过度产生。氧化应激诱导的细胞损伤涉及多聚（ADP - 核糖）聚合酶（PARP）的激活。我们采用基因敲除或使用新型强效菲啶酮PARP抑制剂PJ34（N - （氧代 - 5,6 - 二氢 - 菲啶 - 2 - 基） - N，N - 二甲基乙酰胺盐酸盐）进行药理学抑制的双重方法来抑制PARP - 1，研究内毒素休克时心脏功能受损是否依赖于PARP途径。腹腔注射55 mg/kg大肠杆菌内毒素（脂多糖，LPS）可导致大鼠和小鼠的收缩压和舒张压收缩功能严重降低、心动过速以及平均动脉血压下降。用PJ34治疗可显著改善心脏功能并提高啮齿动物的存活率。此外，与野生型同窝小鼠（PARP（+/ +））相比，PARP - 1基因敲除小鼠（PARP（ - / - ））中LPS诱导的左心室功能抑制明显不那么明显。因此，心血管系统中PARP的激活是内毒素休克相关心脏衰竭和死亡的一个重要促成因素。
