Division of Cardiology, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
Toxicol Appl Pharmacol. 2012 Mar 15;259(3):346-54. doi: 10.1016/j.taap.2012.01.013. Epub 2012 Jan 25.
Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22(phox), p47(phox), p67(phox), NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H2O2. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety.
阿司匹林（乙酰水杨酸，ASA）是一种常用的药物，具有镇痛和解热作用。最近的研究表明，ASA 不仅可以阻断环氧化酶，还可以抑制 NADPH 氧化酶和由此产生的活性氧（ROS）的产生，这一途径是包括高血压和损伤后组织重塑在内的几种疾病的发病机制。在这些疾病状态下，血管紧张素 II（Ang II）通过其 1 型受体（AT1R）激活 NADPH 氧化酶，导致成纤维细胞生长和胶原合成。在这项研究中，我们研究了 ASA 是否会抑制 Ang II 刺激的 NADPH 氧化酶激活、AT1R 转录上调以及随后的胶原生成在小鼠心肌成纤维细胞中的作用。分离并培养小鼠心脏成纤维细胞，并用 Ang II 和/或 ASA 处理。正如预期的那样，Ang II 诱导了 AT1R 的表达，并刺激了心肌成纤维细胞的生长和胶原合成。AT1R 阻滞剂氯沙坦减弱了 Ang II 的这些作用。与氯沙坦类似，ASA 和其 SA 部分抑制了 Ang II 介导的 AT1R 转录以及成纤维细胞增殖和胶原和 MMP 的表达。ASA 还抑制 NADPH 氧化酶亚基（p22(phox)、p47(phox)、p67(phox)、NOX2 和 NOX4）的表达和 ROS 的产生。ASA 不影响总 NF-κB p65，但抑制其磷酸化和激活。这些观察结果表明，ASA 抑制 Ang II 诱导的 NADPH 氧化酶表达、NF-κB 激活和 AT1R 转录在心肌成纤维细胞中，并抑制成纤维细胞增殖和胶原表达。在 ASA 也抑制 H2O2 刺激的心肌成纤维细胞中 AT1R 转录的实验中，NADPH 氧化酶活性在刺激 AT1R 转录中的关键作用变得明显。由于 SA 对 AT1R 表达的作用与 ASA 相似，因此我们认为 ASA 的作用是由其 SA 部分介导的。
