低尿酸促进高血压脑出血的作用及机制研究

Nowadays, hypertensive cerebral hemorrhage is major health burden while its mechanism has not been clarified. With the untargeted metabolome, we have found that serum uric acid (SUA), as an endogenous antioxidant, promoting the smooth muscle cell proliferation, was significantly reduced in the relapse group of hypertensive cerebral hemorrhage compared to hypertensive cerebral hemorrhage group. A study from Israel showed that lower SUA level may increase the risk of cerebral hemorrhage; and may be oxidative stress and smooth muscle cells disappeared are the important reason for hypertension cerebral hemorrhage. According to these results, we hypothesized that lower SUA can reduce the antioxidant ability for our body, inhibit smooth muscle cell proliferation and promote hypertension cerebral hemorrhage. To test this hypothesis, firstly, we analyzed the link between SUA level and hemorrhage relapse, cardiovascular and cerebrovascular events in hypertension cerebral hemorrhage patients, which are our long follow-up patients. We also compared SUA level between hypertensive cerebral hemorrhage group and control group. Secondly, we will test if lower SUA can promote hypertensive cerebral hemorrhage or not in low hypertension animal model. Then, we will study the mechanism for lower SUA promoting hypertensive cerebral hemorrhage in vascular and cellular and molecular levels. Finally, with the data of our long follow-up hypertension patients, we will further confirm the risk relationship between lower SUA and hypertensive intracerebral hemorrhage. Our study will help clarify the mechanism of hypertensive cerebral hemorrhage, and provide new clues for the prevention and treatment of hypertensive cerebral hemorrhage.

高血压脑出血造成重大健康负担，其机制远未阐明。我们前期利用非靶向代谢组学发现尿酸（内源性抗氧化剂、促进平滑肌细胞增殖）在高血压脑出血复发组显著降低，来自以色列的研究提示低尿酸可能增加脑出血发生风险，氧化应激与平滑肌细胞减少或消失是高血压脑血管病变导致出血的重要原因。据此我们推测低尿酸可能通过降低机体抗氧化能力及抑制平滑肌细胞增殖从而促进高血压脑出血发生。为验证此假设，我们拟首先在高血压脑出血随访的样本中分析尿酸水平及其与高血压脑出血复发及心脑血管事件的关系，比较高血压脑出血与对照之间的尿酸水平，在整体动物中检测高血压条件下低尿酸是否促进高血压脑出血的发生，然后在血管、细胞及分子层面解析低尿酸引起高血压脑血管病变的机制，最后，利用已经建立的高血压人群进行随访，进一步确证低尿酸与高血压脑出血发病风险的关系。从而进一步理解高血压脑出血脑血管病变机制，为高血压脑出血的防治提供新的线索。

研究背景及意义.脑卒中严重威胁国人健康，出血性脑卒中（ICH）虽然发病率远低于缺血性脑卒中，但其预后更差，且死亡率和病残率均高于缺血性脑卒中。其中高血压是导致出血性脑卒中的最常见原因。既往研究表明，血清高尿酸水平是高血压、心血管疾病、肾脏病以及缺血性脑卒中的独立危险因素。然而，最近的研究表明血尿酸水平与心脑血管疾病死亡率之间呈U型曲线或J型曲线。低尿酸也可能是心脑血管疾病的危险因素。低尿酸水平与高血压脑出血之间的关系尚无定论。目前，关于高血压脑出血的研究大多聚焦于脑出血后的神经损伤和修复，对于高血压脑出血的病理进程中脑血管的病理变化及其可能的分子机制，我们仍知之甚少。.研究内容.利用非靶向代谢组学技术分析高血压脑出血组及随访后复发组血浆中小分子代谢物差异，比较了对照组、卒中组（脑梗组、腔梗组及高血压脑出血组）尿酸水平差异。分析尿酸水平与高血压脑出血复发及心脑血管疾病死亡风险的关系。建立了低尿酸高血压脑出血模型，利用HE染色以及免疫荧光染色，观察高血压脑出血小鼠脑血管病理形态的改变；分离小鼠的脑血管进行转录组测序，利用生信分析筛选低尿酸引起高血压脑血管病变的关键通路，利用组织切片在脑血管原位利用免疫荧光进行蛋白水平表达验证。.结果.1. 非靶向代谢组学数据表明高血压脑出血组与复发组其小分子代谢物存在显著差异，并且尿酸在高血压脑出血复发组中显著低于高血压脑出血组。.2. 人群研究结果表明，高血压脑出血组的尿酸水平显著低于对照组；而脑卒中其他的两种类型脑梗、腔梗与对照组尿酸水平相比无显著差异。在年龄大于60岁的ICH患者中，低尿酸（二分位， 236 mol/L）增加了高血压脑出血复发的风险。此外，低尿酸也增加了60岁以上ICH患者的心脑血疾病死亡的风险。.3. 我们首次成功建立了低尿酸小鼠模型，并在此基础上建立了低尿酸高血压脑出血模型。.结论.1. 在60岁以上的老年ICH患者中，低血尿酸水平显著增加高血压脑出血复发风险和心脑血管病死亡风险。.2. p-Erk1/2-MMPs信号轴的活性在低尿酸促进高血压脑出血的发生和进展的病理机制中起中心作用。