Arsenic exposure through drinking water is widespread and well-associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which inorganic arsenic (iAS) induces these effects are largely unknown. Recently, an epidemiological study in an American population with a low burden of cardiovascular risk factors found that iAS exposure was associated with altered left ventricular geometry. Considering the possibility that iAS directly induces cardiac remodeling independent of hypertension, we investigated the impact of an environmentally relevant iAS exposure on the structure and function of male and female hearts. Adult male and female C56BL/6J mice were exposed to 615 μg/L iAS for eight weeks. Males exhibited increased systolic blood pressure via tail cuff photoplethysmography, left ventricular wall thickening via transthoracic echocardiography, and increased plasma atrial natriuretic peptide via enzyme immunoassay. RT-qPCR revealed increased myocardial RNA transcripts of Acta1, Myh7, and Nppa, and decreased Myh6, providing evidence of pathological hypertrophy in the male heart. Similar changes were not detected in females, and nitric oxide dependent mechanisms of cardioprotection in the heart appeared to remain intact. Further investigation found that Rcan1 was upregulated in male hearts and that iAS activated NFAT in HEK293 cells via luciferase assay. Interestingly, iAS induced similar hypertrophic gene expression changes in neonatal rat ventricular myocytes, which were blocked by calcineurin inhibition, suggesting that iAS may induce pathological cardiac hypertrophy in part by targeting the calcineurin-NFAT pathway. As such, these results highlight iAS exposure as an independent cardiovascular risk factor and provide biological impetus for its removal from human consumption.

中文翻译：

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无机砷诱发心脏性别依赖性病理性肥大


通过饮用水接触砷的情况很普遍，并且与不良心血管后果密切相关，但无机砷（iAS）引起这些影响的病理生理机制在很大程度上尚不清楚。最近，一项针对心血管危险因素负担较低的美国人群的流行病学研究发现，iAS 暴露与左心室几何结构的改变有关。考虑到 iAS 直接诱导心脏重塑的可能性与高血压无关，我们研究了环境相关的 iAS 暴露对男性和女性心脏结构和功能的影响。成年雄性和雌性 C56BL/6J 小鼠暴露于 615 μg/L iAS 中八周。通过尾套光电体积描记法显示男性收缩压升高，通过经胸超声心动图显示左心室壁增厚，通过酶免疫测定显示血浆心房钠尿肽增加。 RT-qPCR 显示心肌 RNA 转录本 Acta1、Myh7 和 Nppa 增加，Myh6 减少，这提供了男性心脏病理性肥大的证据。在女性中没有检测到类似的变化，心脏中一氧化氮依赖性的心脏保护机制似乎保持完整。进一步研究发现，Rcan1 在男性心脏中表达上调，并且 iAS 通过荧光素酶检测激活 HEK293 细胞中的 NFAT。有趣的是，iAS 在新生大鼠心室肌细胞中诱导了类似的肥大基因表达变化，而这种变化被钙调神经磷酸酶抑制所阻断，这表明 iAS 可能部分通过靶向钙调神经磷酸酶-NFAT 通路来诱导病理性心脏肥大。 因此，这些结果强调了 iAS 暴露是一个独立的心血管危险因素，并为将其从人类消费中去除提供了生物学动力。