Low Serum Uric Acid Levels Promote Hypertensive Intracerebral Hemorrhage by Disrupting the Smooth Muscle Cell-Elastin Contractile Unit and Upregulating the Erk1/2-MMP Axis
Low Serum Uric Acid Levels Promote Hypertensive Intracerebral Hemorrhage by Disrupting the Smooth Muscle Cell-Elastin Contractile Unit and Upregulating the Erk1/2-MMP Axis
复制标题
低血清尿酸水平通过破坏平滑肌细胞-弹性蛋白收缩单位和上调 Erk1/2-MMP 轴促进高血压脑出血
DOI：
10.1007/s12975-020-00791-3
复制
发表时间：
2020-04-22
影响因子：
6.9
通讯作者：
Chen, Jing-zhou
中科院分区：
文献类型：
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作者：
Xiao, Ning;Liu, Tian-long;Chen, Jing-zhou
脑出血（ICH）是一种致死率高的灾难性卒中，其发病机制尚不清楚。以往的研究表明，高血清尿酸（SUA）水平是高血压、心血管疾病（CVD）和缺血性卒中的独立危险因素。然而，我们的代谢组学数据显示，SUA水平在复发性脑出血（R-ICH）患者中低于ICH患者，表明较低的SUA可能有助于ICH。在这项研究中，我们证实了低SUA水平与高血压患者ICH复发风险和心脑血管死亡率之间的相关性。为了确定低SUA影响ICH发病机制的机制，我们开发了第一个低SUA小鼠模型，并对ICH小鼠的脑血管系统进行了转录组分析。当将这些评估与病理形态学相结合时，我们发现低SUA水平导致血管紧张素II（Ang II）诱导的高血压小鼠ICH，并加重ICH的病理进展。体外实验结果表明，p-Erk 1/2-MMP轴参与了UA诱导的低水平弹性蛋白降解，生理浓度的UA和p-Erk 1/2特异性抑制剂具有保护作用。这是首次报道脑出血时平滑肌细胞（SMC）-弹性蛋白收缩单位的破坏。最重要的是，我们发现p-Erk 1/2-MMP轴的上调，促进弹性蛋白的降解，在介导低SUA水平以加剧ICH过程中的脑血管破裂中起着至关重要的作用。
Intracerebral hemorrhage (ICH) is a catastrophic stroke with high mortality, and the mechanism underlying ICH is largely unknown. Previous studies have shown that high serum uric acid (SUA) levels are an independent risk factor for hypertension, cardiovascular disease (CVD), and ischemic stroke. However, our metabolomics data showed that SUA levels were lower in recurrent intracerebral hemorrhage (R-ICH) patients than in ICH patients, indicating that lower SUA might contribute to ICH. In this study, we confirmed the association between low SUA levels and the risk for recurrence of ICH and for cardiac-cerebral vascular mortality in hypertensive patients. To determine the mechanism by which low SUA effects ICH pathogenesis, we developed the first low SUA mouse model and conducted transcriptome profiling of the cerebrovasculature of ICH mice. When combining these assessments with pathological morphology, we found that low SUA levels led to ICH in mice with angiotensin II (Ang II)-induced hypertension and aggravated the pathological progression of ICH. In vitro, our results showed that p-Erk1/2-MMP axis were involved in the low UA-induce degradation of elastin, and that physiological concentrations of UA and p-Erk1/2-specific inhibitor exerted a protective role. This is the first report describing to the disruption of the smooth muscle cell (SMC)-elastin contractile units in ICH. Most importantly, we revealed that the upregulation of the p-Erk1/2-MMP axis, which promotes the degradation of elastin, plays a vital role in mediating low SUA levels to exacerbate cerebrovascular rupture during the ICH process.