Fu Min, Li Yuan, Liu Jingjing, Liu Junjie, Wei Jiaoxia, Qiao Yuxin, Zhong Hanxin, Han Dongyang, Lu Haitao, Yao Li
Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
School of Chinese Medicine, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Traditional Chinese Medicine Phenome Research Center, Hong Kong Baptist University, Hong Kong, 999077, China.
Chin Med. 2024 Dec 19;19(1):173. doi: 10.1186/s13020-024-01039-0.
Pulmonary hypertension (PH) is a severe cardio-pulmonary vascular disease, involves complex molecular mechanism especially during the pathological process of pulmonary vascular remodeling, brings a significant challenge to clinical treatment and thus resulting in high mortality rates. Classic Traditional Chinese medicine formula, Zhishi Xiebai Guizhi Decoction (ZXGD), holds therapeutic potential for PH. In present study, we sought to explore therapeutic potential of ZXGD against PH in rats.
We employed a combination methods of chemical profiling, echocardiographic, morphologic measurements, molecular biology, rats models and cultured pulmonary artery smooth muscle cells (PASMCs) to achieve this.
Eighteen compounds were precisely identified in ZXGD using UHPLC-QTOF-MS/MS. Our data demonstrated ZXGD could alleviate PH by reducing pulmonary artery pressure and alleviating pulmonary vascular remodeling in rats. Specifically, ZXGD was found to intervene in abnormal expansion of PASMCs, thereby attenuating pulmonary vascular remodeling. ZXGD was also observed to modulate expressions of HIF-1α, ROS, and Nrf2 to alleviate hypoxia and oxidative stress. Additionally, ZXGD significantly regulated disorders in pro-inflammatory cytokines, thus mitigating inflammation. Furthermore, ZXGD decreased levels of decadienyl-L-carnitine and LDL-C, while elevating HDL-C and lipid droplet counts, thereby reducing cholesterol and lipid toxicity and preserving mitochondrial function. Importantly, inhibition of HIF-1α reversed expression of key pathological triggers for pulmonary vascular remodeling. Neohesperidin and naringin in ZXGD extract were identified as the primary contributors to its pharmacological effects against PH.
Altogether, our study empirically explored therapeutic potential and pharmacological mechanisms of ZXGD in treating PH, offering a groundwork for the development of novel anti-PH drugs.
肺动脉高压（PH）是一种严重的心肺血管疾病，涉及复杂的分子机制，尤其是在肺血管重塑的病理过程中，给临床治疗带来了重大挑战，导致死亡率很高。经典的中药方剂枳实薤白桂枝汤（ZXGD）对PH具有治疗潜力。在本研究中，我们试图探索ZXGD对大鼠PH的治疗潜力。
我们采用了化学图谱分析、超声心动图、形态学测量、分子生物学、大鼠模型和培养的肺动脉平滑肌细胞（PASMCs）等多种方法来实现这一目标。
使用超高效液相色谱-四极杆飞行时间质谱联用仪（UHPLC-QTOF-MS/MS）在ZXGD中精确鉴定出18种化合物。我们的数据表明，ZXGD可以通过降低大鼠肺动脉压力和减轻肺血管重塑来缓解PH。具体而言，发现ZXGD可干预PASMCs的异常增殖，从而减轻肺血管重塑。还观察到ZXGD可调节缺氧诱导因子-1α（HIF-1α）、活性氧（ROS）和核因子E2相关因子2（Nrf2）的表达，以减轻缺氧和氧化应激。此外，ZXGD显著调节促炎细胞因子的紊乱，从而减轻炎症。此外，ZXGD降低了癸二烯基-L-肉碱和低密度脂蛋白胆固醇（LDL-C）的水平，同时提高了高密度脂蛋白胆固醇（HDL-C）和脂滴数量，从而降低胆固醇和脂质毒性并维持线粒体功能。重要的是，抑制HIF-1α可逆转肺血管重塑关键病理触发因素的表达。ZXGD提取物中的新橙皮苷和柚皮苷被确定为其抗PH药理作用的主要贡献者。
总之，我们的研究实证性地探索了ZXGD治疗PH的治疗潜力和药理机制，为开发新型抗PH药物奠定了基础。
