Institute of Biomedical Engineering, National Cheng-Kung University, and Divison of Cardiovascular Surgery, Chia-yi Christian Hospital, Chia-yi City, Taiwan.
Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H1107-17. doi: 10.1152/ajpheart.01071.2010. Epub 2011 May 27.
Hyperuricemia is associated with cardiovascular disease, but it is usually considered a marker rather than a risk factor. Previous studies using uric acid-lowering drugs in normouricemic animals are not suitable to answer the effect of hyperuricemia on ventricular remodeling after myocardial infarction. The purpose of this study was to determine whether hyperuricemia adversely affects ventricular remodeling in infarcted rats with elevated uric acid. Male Wistar rats aged 8 wk were randomly assigned into either vehicle, oxonic acid, oxonic acid + allopurinol, oxonic acid + benzbromarone, oxonic acid + ABT-627, or oxonic acid + tempol for 4 wk starting 24 h after ligation. Postinfarction was associated with increased oxidant production, as measured by myocardial superoxide, isoprostane, xanthine oxidase activity, and dihydroethidium staining. Compared with normouricemic infarcted rats, hyperuricemic infarcted rats had a significant increase of superoxide production (1.7×) and endothelin-1 protein (1.2×) and mRNA (1.4×) expression, which was associated with increased left ventricular dysfunction and enhanced myocardial hypertrophy and fibrosis. These changes were all prevented by treatment with allopurinol. For similar levels of urate lowering, the uricosuric agent benzbromarone had no effect on ventricular remodeling. In spite of equivalent hyperuricemia, the ability of both ABT-627 and tempol to attenuate ventricular remodeling suggested involvement of endothelin-1 and redox pathways. Hyperuricemia is associated with unfavorable ventricular remodeling probably through a superoxide and endothelin-1-dependent pathway. Uric acid lowering without inhibition of superoxide and endothelin-1 may not have an effect on remodeling. Chronic administration of allopurinol, ABT-627, and tempol is associated with attenuated ventricular remodeling.
高尿酸血症与心血管疾病有关，但通常被认为是一个标志物而不是危险因素。以前在尿酸正常的动物中使用降低尿酸的药物的研究并不适合回答高尿酸血症对心肌梗死后心室重构的影响。本研究旨在确定高尿酸血症是否对尿酸升高的梗死大鼠的心室重构产生不利影响。雄性 Wistar 大鼠在结扎后 24 小时开始随机分为对照组、氧嗪酸钾组、氧嗪酸钾+别嘌醇组、氧嗪酸钾+苯溴马隆组、氧嗪酸钾+ ABT-627 组和氧嗪酸钾+替米沙坦组，分别接受相应药物治疗 4 周。与尿酸正常的梗死大鼠相比，高尿酸血症梗死大鼠的超氧化物产生（增加 1.7 倍）和内皮素-1 蛋白（增加 1.2 倍）和 mRNA（增加 1.4 倍）表达显著增加，这与左心室功能障碍增加和心肌肥大和纤维化增强有关。这些变化均通过别嘌醇治疗得到预防。对于类似的尿酸降低水平，促尿酸排泄药苯溴马隆对心室重构没有影响。尽管尿酸水平相同，ABT-627 和替米沙坦减轻心室重构的能力表明内皮素-1 和氧化还原途径的参与。高尿酸血症与不良的心室重构有关，可能是通过超氧化物和内皮素-1 依赖途径。不抑制超氧化物和内皮素-1 的尿酸降低可能对重构没有影响。别嘌醇、ABT-627 和替米沙坦的慢性给药与减轻的心室重构有关。
