Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction.
Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction.
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DOI：
10.1161/jaha.115.002023
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发表时间：
2015-10-09
影响因子：
5.4
通讯作者：
Shibata H
中科院分区：
文献类型：
--
作者：
Aoki K;Teshima Y;Kondo H;Saito S;Fukui A;Fukunaga N;Nawata T;Shimada T;Takahashi N;Shibata H
肾功能不全是房颤（AF）的主要危险因素。尿毒症毒素硫酸吲哚酚可能导致心脏纤维化和AF底物在肾功能不全中的进展。将雄性Sprague-Dawley大鼠随机分配至以下组：5/6肾切除术（5/6 Nx）（含溶剂）、5/6 Nx（含AST-120）、假手术（含溶剂）和假手术（含AST-120）。给予溶剂和AST-120 4周。5/6 Nx组血清IS水平显著升高。5/6 Nx组左心房中氧化应激指标丙二醛的表达上调，并伴有NADPH氧化酶2和4表达的增加。单核细胞介导的炎症信号，如CD 68，单核细胞趋化蛋白1和血管细胞粘附分子1也在5/6 Nx组中上调。在5/6 Nx组的左心房组织中，间质纤维化不均匀地促进，促纤维化指标如转化生长因子β1、α-平滑肌肌动蛋白和1型胶原蛋白的表达上调。在培养的心房成纤维细胞中，与IS一起孵育上调了氧化应激、炎症和促纤维化因子的标志物的表达。这些结果表明IS对AF底物的进展有直接影响。在电生理实验中，5/6 Nx组的心房外刺激均能诱发房颤。AST-120治疗可显著缓解肾功能不全诱导的氧化应激、炎症和心房纤维化，从而减弱AF诱导。硫酸吲哚酚促进心房纤维化和AF，因此是预防肾功能不全诱导的AF的新治疗靶点。
Renal dysfunction is a major risk factor for atrial fibrillation (AF). The uremic toxin indoxyl sulfate may contribute to the progression of cardiac fibrosis and AF substrate in renal dysfunction. Male Sprague–Dawley rats were assigned randomly to the following groups: 5/6 nephrectomy (5/6Nx) with vehicle, 5/6Nx with AST‐120, sham procedure with vehicle, and sham procedure with AST‐120. Vehicle and AST‐120 were administered for 4 weeks. Serum levels of IS were significantly increased in 5/6Nx groups. Expression of malondialdehyde, an indicator of oxidative stress, was upregulated in the left atrium of 5/6Nx groups and was accompanied by an increase in expression of NADPH oxidase 2 and 4. Monocyte‐mediated inflammatory signals such as CD68, monocyte chemoattractant protein 1, and vascular cell adhesion molecule 1 were also upregulated in 5/6Nx groups. Interstitial fibrosis was promoted heterogeneously, and expression of profibrotic indicators such as transforming growth factor β1, α‐smooth muscle actin, and collagen type 1 was upregulated in left atrium tissue of 5/6Nx groups. In cultured atrial fibroblasts, incubation with IS upregulated expression of the markers of oxidative stress, inflammation, and profibrotic factors. These results suggest the direct effects of IS on the progression of AF substrate. AF was consistently and invariably induced by atrial extrastimuli in 5/6Nx groups in electrophysiological experiments. AST‐120 treatment significantly alleviated renal dysfunction–induced oxidative stress, inflammation, and atrial fibrosis and, consequently, attenuated AF inducibility. Indoxyl sulfate facilitates atrial fibrosis and AF and thus is a novel therapeutic target for prevention of renal dysfunction–induced AF.