Aldehyde dehydrogenase 2 (ALDH2), a pivotal enzyme in the metabolism of toxic aldehydes produced by oxidative stress, has been demonstrated to play a cardioprotective role in cardiovascular diseases. Antrodia cinnamomea triterpenoids (ACT) is a medicinal mushroom with anti-inflammatory and antioxidant properties, and our previous study found that ACT can exert anti-fatty liver effects by regulating ALDH2. This study aimed to elucidate the impact of ACT and its monomer on cardiac hypertrophy and investigate the relationship between its pharmacological mechanism and ALDH2. Through examining cardiac morphology and expression levels of hypertrophic biomarkers, ACT significantly reduced myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC)surgery in wild-type mice, but not in ALDH2 knockout mice. In vitro, ACT and its monomeric dehydrosulphurenic acid (DSA) inhibited the hypertrophic phenotype of Ang II-stimulated neonatal cardiac myocytes (NRCMs) in an ALDH2-dependent manner. Regarding the pharmacological mechanism, it was observed that ACT and DSA restored ALDH2 expression and activity in myocardial tissues of WT-Ang II/TAC mice and Ang II-induced NRCMs. Furthermore, it inhibited oxidative stress and improved mitochondrial quality control (MQC) homeostasis in an ALDH2-dependent manner. We screened SNW1, a transcriptional coactivator, as a DSA-binding protein by “target fishing” and cellular enthusiasm transfer assay techniques and validated that SNW1 promoted ALDH2 transcription and translation levels through synergistic interaction with the transcription factor RXR. In conclusion, the findings demonstrate that ACT/DSA upregulates ALDH2 expression via regulating SNW1/RXR, thereby inhibiting oxidative stress and maintaining MQC homeostasis, and then protects against cardiac hypertrophy.

中文翻译：

---

牛樟芝三萜类化合物通过 SNW1/RXR/ALDH2 轴减轻心脏肥大


醛脱氢酶 2 （ALDH2） 是氧化应激产生的有毒醛代谢中的关键酶，已被证明在心血管疾病中起心脏保护作用。牛樟芝三萜类化合物 （ACT） 是一种具有抗炎和抗氧化特性的药用蘑菇，我们之前的研究发现 ACT 可以通过调节 ALDH2 发挥抗脂肪肝作用。本研究旨在阐明 ACT 及其单体对心脏肥大的影响，并探讨其药理机制与 ALDH2 的关系。通过检查心脏形态和肥厚生物标志物的表达水平，ACT 显着降低了血管紧张素 II （Ang II） 和横主动脉收缩 （TAC） 手术在野生型小鼠中诱导的心肌肥大，但在 ALDH2 敲除小鼠中没有。在体外，ACT 及其单体脱硫磺酸 （DSA） 以 ALDH2 依赖性方式抑制 Ang II 刺激的新生儿心肌细胞 （NRCMs） 的肥大表型。在药理机制方面，观察到 ACT 和 DSA 恢复了 WT-Ang II/TAC 小鼠和 Ang II 诱导的 NRCM 小鼠心肌组织中 ALDH2 的表达和活性。此外，它以 ALDH2 依赖性方式抑制氧化应激并改善线粒体质量控制 （MQC） 稳态。我们通过 “target fishing” 和细胞热情转移测定技术筛选了转录共激活因子 SNW1 作为 DSA 结合蛋白，并验证了 SNW1 通过与转录因子 RXR 的协同相互作用促进 ALDH2 转录和翻译水平。 总之，研究结果表明，ACT/DSA 通过调节 SNW1/RXR 上调 ALDH2 表达，从而抑制氧化应激和维持 MQC 稳态，进而防止心脏肥大。