Abstract：
Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, could be a promising candidate to treat acute myocardial infarction (AMI). In this study, AMI was induced in New Zealand White rabbits by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. The animals were distributed into three experimental groups: the sham-operated group (SHAM), the AMI group and the AMI + VPA group (AMI treated with VPA 500 mg/kg/day). After 5 weeks, abdominal aorta was removed and used for isometric recording of tension in organ baths or protein expression by Western blot, and plasma for the determination of nitrate/nitrite (NOx) levels by colorimetric assay. Our results indicated that AMI induced a reduction of the endothelium-dependent response to acetylcholine without modifying the endothelium-independent response to sodium nitroprusside, leading to endothelial dysfunction. VPA treatment reversed AMI-induced endothelial dysfunction and even increased NO sensitivity in vascular smooth muscle. This response was consistent with an antioxidant effect of VPA, as it was able to reverse the superoxide dismutase 1 (SOD 1) down-regulation induced by AMI. Our experiments also ruled out that the VPA mechanism was related to eNOS, iNOS, sGC and arginase expression or changes in NOx plasma levels. Therefore, we conclude that VPA improves vasodilation by increasing NO bioavailability, likely due to its antioxidant effect. Since endothelial dysfunction was closely related to AMI, VPA treatment could increase aortic blood flow, making it a potential agent in reperfusion therapy that can prevent the vascular damage.
摘要：
丙戊酸钠(VPA),组蛋白去乙酰化酶（HDAC）抑制剂，可能是治疗急性心肌梗死（AMI）的有希望的候选人。在这项研究中,通过闭塞左回旋支冠状动脉1小时，在新西兰白兔中诱发AMI，其次是再灌注。将动物分为三个实验组：假手术组（SHAM），AMI组和AMI+VPA组(用VPA500mg/kg/天治疗的AMI)。5周后,切除腹主动脉，并通过Westernblot等轴测记录器官浴中的张力或蛋白质表达，和血浆，用于通过比色法测定硝酸盐/亚硝酸盐（NOx）水平。我们的结果表明，AMI诱导了对乙酰胆碱的内皮依赖性反应的减少，而不改变对硝普钠的内皮依赖性反应，导致内皮功能障碍。VPA治疗可逆转AMI诱导的内皮功能障碍，甚至增加血管平滑肌的NO敏感性。这种反应与VPA的抗氧化作用一致，因为它能够逆转AMI诱导的超氧化物歧化酶1（SOD1）下调。我们的实验还排除了VPA机制与eNOS有关，iNOS,sGC和精氨酸酶的表达或NOx血浆水平的变化。因此,我们得出的结论是VPA通过增加NO的生物利用度来改善血管舒张，可能是由于其抗氧化作用。由于内皮功能障碍与AMI密切相关，VPA治疗可以增加主动脉血流量，使其成为预防血管损伤的再灌注治疗的潜在药物。
