Guo Zhi, Wu Meizhu, Chen Lingqi, Chen Hong, Wu Jinkong, Xie Qiurong, Lin Guosheng, Lian Dawei, Peng Jun, Shen Aling
Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China.
Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, 350122, China; Overseas Education College, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
Eur J Pharmacol. 2025 May 5;994:177393. doi: 10.1016/j.ejphar.2025.177393. Epub 2025 Feb 15.
Although neferine exhibits obvious therapeutic effects against hypertension, its effects on cardiac protection remain unknown.
This study aimed to investigate its potential cardioprotective effects and associated mechanisms.
Spontaneously hypertensive rats (SHRs) were randomly divided into four groups, namely SHR, SHR + Neferine-L (2.5 mg/kg/day), SHR + Neferine-M (5 mg/kg/day), and SHR + Neferine-H (10 mg/kg/day). Wistar Kyoto rats were used as control. Various concentrations of neferine or double distilled water were then administered intragastrically for 10 weeks. Thereafter, cardiac function, pathological changes, cell apoptosis, and reactive oxygen species (ROS) accumulation, as well as their underlying mechanisms, were evaluated in SHRs and/or hypoxia-induced H9c2 cells.
Neferine treatment significantly mitigated the decrease in left ventricular ejection fraction and fractional shortening and increase in left ventricular mass, end-systolic volume, and cardiac injury in SHRs. In SHR cardiac tissues, neferine treatment reversed 154 upregulated and 108 and downregulated transcripts. Pathway enrichment analysis found that multiple pathways were commonly enriched, including the apoptosis, PI3K-Akt, MAPK, and HIF-1 pathways. Consistently, neferine treatment significantly mitigated cardiomyocyte apoptosis, restored mitochondrial membrane depolarization, and reduced ROS accumulation. Mechanistically, neferine treatment significantly decreased the phosphorylation of ERK, p38 MAPK, and JNK; the Bax/Bcl-2 ratio; and the expression of HIF-1α, NADPH oxidase 4, and cleaved caspases-3 and -9 but increased the phosphorylation of PI3K and Akt and the expression of CD31.
Neferine treatment effectively mitigated hypertensive cardiomyocyte apoptosis and attenuated the abnormal activation of multiple signaling pathways, including the PI3K/Akt, MAPK, and HIF-1 pathways.
尽管甲基莲心碱对高血压具有明显的治疗作用，但其对心脏的保护作用仍不清楚。
本研究旨在探讨其潜在的心脏保护作用及相关机制。
将自发性高血压大鼠（SHR）随机分为四组，即SHR组、SHR + 低剂量甲基莲心碱组（2.5毫克/千克/天）、SHR + 中剂量甲基莲心碱组（5毫克/千克/天）和SHR + 高剂量甲基莲心碱组（10毫克/千克/天）。以Wistar Kyoto大鼠作为对照。然后将不同浓度的甲基莲心碱或双蒸水灌胃给药10周。此后，在SHR和/或缺氧诱导的H9c2细胞中评估心脏功能、病理变化、细胞凋亡、活性氧（ROS）积累及其潜在机制。
甲基莲心碱治疗显著减轻了SHR左心室射血分数和缩短分数的降低以及左心室质量、收缩末期容积和心脏损伤的增加。在SHR心脏组织中，甲基莲心碱治疗逆转了154个上调和108个下调的转录本。通路富集分析发现多个通路共同富集，包括凋亡、PI3K-Akt、MAPK和HIF-1通路。同样，甲基莲心碱治疗显著减轻了心肌细胞凋亡，恢复了线粒体膜去极化，并减少了ROS积累。机制上，甲基莲心碱治疗显著降低了ERK、p38 MAPK和JNK的磷酸化；Bax/Bcl-2比值；以及HIF-1α、NADPH氧化酶4和裂解的半胱天冬酶-3和-9的表达，但增加了PI3K和Akt的磷酸化以及CD31的表达。
甲基莲心碱治疗有效减轻了高血压心肌细胞凋亡，并减弱了包括PI3K/Akt、MAPK和HIF-1通路在内的多个信号通路的异常激活。
