Lam Lai Kwan, Xu Peng-Li, Xie Peng-Cheng, Liang Qiu-Er, Xie Ting, Poon Lee Yam, Xiao Ya, Chen Li-Guo
School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Front Nutr. 2025 Sep 11;12:1647017. doi: 10.3389/fnut.2025.1647017. eCollection 2025.
Taohong Siwu Decoction (THSWD), a traditional Chinese medicine formula, is increasingly applied in clinical practice for hypertension management. Our previous research demonstrated that THSWD alleviates high-salt-induced hypertension in mice. This study aims to further elucidate the underlying mechanisms of THSWD in treating hypertension.
The chemical composition of THSWD was identified using UPLC-Q/TOF-MS in earlier research. In this study, we performed both and experiments. mice (KO) and C57BL/6 mice (WT) were fed a high-salt diet with or without THSWD treatment. Human aortic endothelial cells (HAECs) were cultured in high-NaCl conditions, with or without ATF4 inhibition. Blood pressure, vascular injury, calcium overload, and ferroptosis were measured to evaluate the protective effects of THSWD.
, a high-salt diet caused hypertension, vascular wall thickening, vascular injury, calcium overload, and ferroptosis, all of which were significantly alleviated by THSWD and the calcium-channel blocker nifedipine (NI). THSWD also reduced the high-salt-induced overexpression of ATF4. Similar effects were observed , where THSWD, the ferroptosis inhibitor ferrostatin-1 (Fer-1), the intracellular calcium chelator BAPTA-AM, and NI improved calcium overload and ferroptosis caused by high-NaCl. This was accompanied by reduced expression of CaMK4, CACNA1C, IP3R, RyR2, GPX4, ACSL4, and LPCAT3. Furthermore, compared to mice on a high-salt diet, those treated with THSWD showed greater reductions in blood pressure, improved vascular endothelial function, and better suppression of calcium overload and ferroptosis. Inhibition of ATF4 or co-treatment with siATF4 and THSWD also restored abnormal biomarker levels (iron, calcium, 12-HETE, 15-HETE, GSH, GSH/GSSG, MDA, and LPO) and normalized calcium overload- and ferroptosis-related markers.
THSWD effectively lowers blood pressure and protects against vascular damage in high-salt-induced hypertension. Its protective effects are achieved by inhibiting calcium overload and ferroptosis through the regulation of ATF4.
桃红四物汤（THSWD）是一种中药配方，在高血压管理的临床实践中应用越来越广泛。我们之前的研究表明，THSWD可减轻小鼠高盐诱导的高血压。本研究旨在进一步阐明THSWD治疗高血压的潜在机制。
在早期研究中使用超高效液相色谱-四极杆/飞行时间质谱（UPLC-Q/TOF-MS）鉴定了THSWD的化学成分。在本研究中，我们进行了体内和体外实验。给自噬相关基因敲除（KO）小鼠和C57BL/6小鼠（野生型，WT）喂食高盐饮食，同时进行或不进行THSWD治疗。在高氯化钠条件下培养人主动脉内皮细胞（HAECs），同时进行或不进行激活转录因子4（ATF4）抑制。测量血压、血管损伤、钙超载和铁死亡，以评估THSWD的保护作用。
在体内，高盐饮食导致高血压、血管壁增厚、血管损伤、钙超载和铁死亡，而THSWD和钙通道阻滞剂硝苯地平（NI）均能显著减轻这些症状。THSWD还降低了高盐诱导的ATF4过表达。在体外也观察到类似的效果，THSWD、铁死亡抑制剂铁抑素-1（Fer-1）、细胞内钙螯合剂1,2-双（2-氨基苯氧基）乙烷-N,N,N′,N′-四乙酸四乙酰氧基甲酯（BAPTA-AM）和NI改善了高氯化钠引起的钙超载和铁死亡。这伴随着钙/钙调蛋白依赖性蛋白激酶4（CaMK4）、L型钙通道α1C亚基（CACNA1C）、三磷酸肌醇受体（IP3R）、兰尼碱受体2（RyR2）、谷胱甘肽过氧化物酶4（GPX4）、长链脂酰辅酶A合成酶4（ACSL4）和溶血磷脂酰胆碱酰基转移酶3（LPCAT3）表达的降低。此外，与高盐饮食的KO小鼠相比，接受THSWD治疗的小鼠血压降低幅度更大，血管内皮功能得到改善，钙超载和铁死亡得到更好的抑制。抑制ATF4或用小干扰RNA（siATF4）与THSWD联合处理也恢复了异常生物标志物水平（铁、钙、12-羟基二十碳四烯酸、15-羟基二十碳四烯酸、谷胱甘肽、谷胱甘肽/氧化型谷胱甘肽、丙二醛和脂质过氧化物），并使钙超载和铁死亡相关标志物正常化。
THSWD可有效降低高盐诱导的高血压患者的血压，并预防血管损伤。其保护作用是通过调节ATF4抑制钙超载和铁死亡来实现的。
