p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes.
p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes.
复制标题
对甲酚硫酸盐通过增强心肌细胞凋亡而加重与慢性肾病相关的心脏功能障碍
DOI：
10.1161/jaha.115.001852
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发表时间：
2015-06-11
影响因子：
5.4
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Han H;Zhu J;Zhu Z;Ni J;Du R;Dai Y;Chen Y;Wu Z;Lu L;Zhang R
背景心血管疾病是慢性肾脏病患者死亡的主要原因。大量证据表明，对甲苯基硫酸盐（PCS），尿毒症毒素，与慢性肾脏疾病患者的心血管死亡率相关;然而，这一特征的分子机制尚未完全阐明。方法和结果我们的目的是确定PCS积累是否会通过对心肌细胞的直接细胞毒性对心功能不全产生不利影响。在接受5/6肾切除术的小鼠中，PCS促进心脏细胞凋亡，并影响超声心动图观察的左室跨瓣早期峰值流速与左室跨瓣晚期峰值流速的比值（E/A比值）（每组n=8）。夹竹桃素，NADPH氧化酶活性的抑制剂，减弱E/A比的这种改变（每组n=6）。PCS还通过上调p22 phox和p47 phox、NADPH氧化酶亚基的表达以及活性氧的产生而在H9 c2细胞中表现出促凋亡特性。夹竹桃麻素和N-乙酰半胱氨酸都能够抑制PCS的作用，这强调了NADPH氧化酶激活对于作用机制的重要性。结论PCS的心脏毒性至少部分归因于诱导的NADPH氧化酶活性和活性氧的产生，促进心肌细胞凋亡，导致舒张功能障碍。
Background Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A body of evidence suggests that p-cresyl sulfate (PCS), a uremic toxin, is associated with the cardiovascular mortality rate of patients with chronic kidney disease; however, the molecular mechanisms underlying this feature have not yet been fully elucidated. Methods and Results We aimed to determine whether PCS accumulation could adversely affect cardiac dysfunction via direct cytotoxicity to cardiomyocytes. In mice that underwent 5/6 nephrectomy, PCS promoted cardiac apoptosis and affected the ratio of left ventricular transmitral early peak flow velocity to left ventricular transmitral late peak flow velocity (the E/A ratio) observed by echocardiography (n=8 in each group). Apocynin, an inhibitor of NADPH oxidase activity, attenuates this alteration of the E/A ratio (n=6 in each group). PCS also exhibited proapoptotic properties in H9c2 cells by upregulating the expression of p22phox and p47phox, NADPH oxidase subunits, and the production of reactive oxygen species. Apocynin and N-acetylcysteine were both able to suppress the effect of PCS, underscoring the importance of NADPH oxidase activation for the mechanism of action. Conclusions This study demonstrated that the cardiac toxicity of PCS is at least partially attributed to induced NADPH oxidase activity and reactive oxygen species production facilitating cardiac apoptosis and resulting in diastolic dysfunction.