Pacher Pal, Mabley Jon G, Soriano Francisco G, Liaudet Lucas, Szabó Csaba
Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA.
Int J Mol Med. 2002 Jun;9(6):659-64.
Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of endothelial dysfunction associated with atherosclerosis, hypertension and aging. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury and circulatory shock. Here we investigated the role of PARP activation in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension and aging. Retired breeder spontaneously hypertensive rats (SHR, 40 weeks old) and apolipoprotein E knockout mice (apoE-Ko, 10 weeks old) were treated for 20 weeks with vehicle or the potent PARP inhibitor PJ34. In the vehicle-treated SHR rats and apoE-Ko mice (kept on atherogenic diet) there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. SHR rats also developed severe hypertension and cardiac hypertrophy. Treatment with the PARP inhibitor did not influence high blood pressure and cardiac hypertrophy in SHR rats, but it improved Ach-induced, NO-mediated vascular relaxation. In addition to the beneficial effects of chronic treatment with PARP inhibitor, 1-h in vitro incubation of aortic rings from SHR rats with PJ34 (3 micromol/l) was also able to improve the endothelial dysfunction. In contrast, in apoE-Ko mice PJ34 treatment did not affect the parameters studied. Thus, PARP activation contributes to the pathogenesis of endothelial dysfunction associated with hypertension and aging, but not in the current experimental model of atherosclerosis.
最近，活性氧和氮物种的产生增加被认为与动脉粥样硬化、高血压和衰老相关的内皮功能障碍的发病机制有关。氧化应激诱导的细胞损伤触发核酶聚（ADP - 核糖）聚合酶（PARP）的激活，而PARP反过来又在包括糖尿病、再灌注损伤和循环性休克在内的各种病理生理条件下导致心脏和血管功能障碍。在此，我们研究了PARP激活在与动脉粥样硬化、高血压和衰老相关的心脏和内皮功能障碍发病机制中的作用。将退休种系自发性高血压大鼠（SHR，40周龄）和载脂蛋白E基因敲除小鼠（apoE - Ko，10周龄）用载体或强效PARP抑制剂PJ34处理20周。在用载体处理的SHR大鼠和apoE - Ko小鼠（维持致动脉粥样硬化饮食）中，通过血管环对乙酰胆碱的舒张反应性测量，内皮功能有显著丧失。SHR大鼠还出现了严重的高血压和心脏肥大。用PARP抑制剂治疗对SHR大鼠的高血压和心脏肥大没有影响，但改善了乙酰胆碱诱导的、一氧化氮介导的血管舒张。除了PARP抑制剂长期治疗的有益作用外，用PJ34（3微摩尔/升）对SHR大鼠的主动脉环进行1小时的体外孵育也能够改善内皮功能障碍。相比之下，在apoE - Ko小鼠中，PJ34治疗对所研究的参数没有影响。因此，PARP激活促成了与高血压和衰老相关的内皮功能障碍的发病机制，但在当前的动脉粥样硬化实验模型中并非如此。
