畅脉乐胶囊调控P4HA1介导动脉粥样硬化斑块稳定性的机制研究
Study on the Mechanism of Changmaile Capsules in Regulating P4HA1-Mediated Atherosclerotic Plaque Stability
DOI: 10.12677/md.2026.165073, PDF,    科研立项经费支持
作者: 张 宽, 翁一玲：福建中医药大学附属第二人民医院药学部，福建 福州；福建省医疗机构中药制剂重点实验室，福建 福州；欧余航：福建中医药大学附属第三人民医院药学部，福建 福州；张松青：福建中医药大学附属第二人民医院药学部，福建 福州
关键词: 畅脉乐胶囊(I)；P4HA1；动脉粥样硬化；斑块稳定性；胶原合成；Changmaile Capsules (I)； P4HA1； Atherosclerosis； Plaque Stability； Collagen Synthesis
摘要: 动脉粥样硬化是心脑血管疾病的核心病理基础，其发生发展与血管内皮损伤、脂质代谢异常、巨噬细胞泡沫化及细胞外基质重塑密切相关。脯氨酰4-羟化酶α亚基1 (Prolyl 4-Hydroxylase Subunit Alpha-1, P4HA1)是胶原合成和缺氧反应的关键酶。在调控血管壁纤维化、斑块稳定性及局部微环境炎症中发挥重要作用。畅脉乐胶囊在改善血管内皮功能、抗动脉粥样硬化方面具有确切疗效。文章系统梳理了动脉粥样硬化中细胞外基质重塑与P4HA1的病理调控机制，并深入探讨了畅脉乐胶囊多靶点、多途径调控P4HA1介导抗动脉粥样硬化的潜在科学内涵，以期为畅脉乐胶囊靶向P4HA1干预动脉粥样硬化提供理论依据。
Abstract: Atherosclerosis serves as the core pathological basis for cardiovascular and cerebrovascular diseases. Its onset and progression are closely associated with vascular endothelial injury, abnormal lipid metabolism, macrophage foam cell formation, and extracellular matrix remodeling. Prolyl 4-hydroxylase subunit alpha-1 (P4HA1) is a key enzyme in collagen synthesis and the hypoxic response, playing a crucial role in regulating vascular wall fibrosis, plaque stability, and inflammation within the local microenvironment. Changmaile Capsules have demonstrated definite efficacy in improving vascular endothelial function and combating atherosclerosis. This paper systematically reviews the pathological regulatory mechanisms linking extracellular matrix remodeling and P4HA1 in atherosclerosis. It explores in depth the potential scientific basis underlying the multi-target and multi-pathway regulation of P4HA1 by Changmaile Capsules in exerting anti-atherosclerotic effects, aiming to provide a theoretical foundation for targeting P4HA1 with Changmaile Capsules to intervene in atherosclerosis.
文章引用：张宽, 欧余航, 张松青, 翁一玲. 畅脉乐胶囊调控P4HA1介导动脉粥样硬化斑块稳定性的机制研究[J]. 医学诊断, 2026, 16(5): 562-569. https://doi.org/10.12677/md.2026.165073

参考文献

[1] Libby, P. (2021) The Changing Landscape of Atherosclerosis. Nature, 592, 524-533.
https://doi.org/10.1038/s41586-021-03392-8
[2] Attiq, A., Afzal, S., Ahmad, W. and Kandeel, M. (2024) Hegemony of Inflammation in Atherosclerosis and Coronary Artery Disease. European Journal of Pharmacology, 966, Article ID: 176338.
https://doi.org/10.1016/j.ejphar.2024.176338
[3] Ross, R. (1999) Atherosclerosis—An Inflammatory Disease. New England Journal of Medicine, 340, 115-126.
https://doi.org/10.1056/nejm199901143400207
[4] Kong, P., Cui, Z., Huang, X., Zhang, D., Guo, R. and Han, M. (2022) Inflammation and Atherosclerosis: Signaling Pathways and Therapeutic Intervention. Signal Transduction and Targeted Therapy, 7, Article No. 131.
https://doi.org/10.1038/s41392-022-00955-7
[5] Di Nubila, A., Dilella, G., Simone, R. and Barbieri, S.S. (2024) Vascular Extracellular Matrix in Atherosclerosis. International Journal of Molecular Sciences, 25, Article 12017.
https://doi.org/10.3390/ijms252212017
[6] Pihlajaniemi, T., Myllylä, R. and Kivirikko, K.I. (1991) Prolyl 4-Hydroxylase and Its Role in Collagen Synthesis. Journal of Hepatology, 13, S2-S7.
https://doi.org/10.1016/0168-8278(91)90002-s
[7] Semenza, G.L. (2012) Hypoxia-Inducible Factors in Physiology and Medicine. Cell, 148, 399-408.
https://doi.org/10.1016/j.cell.2012.01.021
[8] Yang, X., Zhang, D., Li, M., Shao, Y., Zhang, X. and Xue, Y. (2024) P4HA1: An Important Target for Treating Fibrosis Related Diseases and Cancer. Frontiers in Pharmacology, 15, Article 1493420.
https://doi.org/10.3389/fphar.2024.1493420
[9] 张宽, 翁一玲, 张瑜, 严锦贤, 曾茂贵. 畅脉乐胶囊临床合理用药分析[J]. 中医学, 2023, 12(3): 496-501.
[10] 黄松雄, 张玉琴, 刘巧婷, 等. 畅脉乐通过调控PPAR信号通路对动脉粥样硬化大鼠巨噬细胞自噬、血管内皮功能及动脉斑块稳定性相关蛋白影响[J]. 临床医学进展, 2023, 13(10): 16670-16677.
[11] Chen, W., Yu, F., Di, M., Li, M., Chen, Y., Zhang, Y., et al. (2018) MicroRNA-124-3p Inhibits Collagen Synthesis in Atherosclerotic Plaques by Targeting Prolyl 4-Hydroxylase Subunit α-1 (P4HA1) in Vascular Smooth Muscle Cells. Atherosclerosis, 277, 98-107.
https://doi.org/10.1016/j.atherosclerosis.2018.08.034
[12] Kolodgie, F.D., Virmani, R., Burke, A.P., Farb, A., Weber, D.K., Kutys, R., et al. (2004) Pathologic Assessment of the Vulnerable Human Coronary Plaque. Heart, 90, 1385-1391.
https://doi.org/10.1136/hrt.2004.041798
[13] Miano, J.M., Fisher, E.A. and Majesky, M.W. (2021) Fate and State of Vascular Smooth Muscle Cells in Atherosclerosis. Circulation, 143, 2110-2116.
https://doi.org/10.1161/circulationaha.120.049922
[14] Toutouzas, K., Synetos, A., Nikolaou, C., Tsiamis, E., Tousoulis, D. and Stefanadis, C. (2012) Matrix Metalloproteinases and Vulnerable Atheromatous Plaque. Current Topics in Medicinal Chemistry, 12, 1166-1180.
https://doi.org/10.2174/1568026611208011166
[15] Salo, A.M., Rappu, P., Koski, M., Karjalainen, E., Izzi, V., Drushinin, K., et al. (2024) Collagen Prolyl 4-Hydroxylase Isoenzymes I and II Have Sequence Specificity towards Different X-Pro-Gly Triplets. Matrix Biology, 125, 73-87.
https://doi.org/10.1016/j.matbio.2023.12.001
[16] Shi, R., Hu, W., Zhang, Y., Gao, S., Smith, A.H., Ye, J., et al. (2019) Ascorbate Inducible N259 Glycans on Prolyl 4-Hydroxylase Subunit Α1 Promote Hydroxylation and Secretion of Type I Collagen. Cellular and Molecular Life Sciences, 76, 3449-3464.
https://doi.org/10.1007/s00018-019-03081-w
[17] Xu, Y., Xia, D., Huang, K. and Liang, M. (2024) Hypoxia-Induced P4HA1 Overexpression Promotes Post-Ischemic Angiogenesis by Enhancing Endothelial Glycolysis through Downregulating Fbp1. Journal of Translational Medicine, 22, Article No. 74.
https://doi.org/10.1186/s12967-024-04872-x
[18] Van Den Diepstraten, C., Papay, K., Bolender, Z., Brown, A. and Pickering, J.G. (2003) Cloning of a Novel Prolyl 4-Hydroxylase Subunit Expressed in the Fibrous Cap of Human Atherosclerotic Plaque. Circulation, 108, 508-511.
https://doi.org/10.1161/01.cir.0000080883.53863.5c
[19] Huang, X.Z., Liu, X.X., Song, J.T., Wang, L., Liu, X.L., Qu, H.Y., et al. (2015) Prolyl-4-Hydroxylase-α1 Improves the Stability of Advanced Plaques but Accelerates the Atherosclerotic Lesion Formation of Early Plaques. European Heart Journal Supplements, 17, C49-C58.
https://doi.org/10.1093/eurheartj/suv028
[20] Cao, X.Q., Liu, X.X., Li, M.M., Zhang, Y., Chen, L., Wang, L., et al. (2016) Overexpression of Prolyl-4-Hydroxylase-α1 Stabilizes but Increases Shear Stress-Induced Atherosclerotic Plaque in Apolipoprotein E-Deficient Mice. Disease Markers, 2016, Article ID: 1701637.
https://doi.org/10.1155/2016/1701637
[21] Zhang, K., Huang, X., Li, X., Feng, M., Li, L., Cai, X., et al. (2012) Interleukin 6 Destabilizes Atherosclerotic Plaques by Downregulating Prolyl-4-Hydroxylase Α1 via a Mitogen-Activated Protein Kinase and C-Jun Pathway. Archives of Biochemistry and Biophysics, 528, 127-133.
https://doi.org/10.1016/j.abb.2012.09.007
[22] Li, L., Cai, X., Feng, M., Rong, Y., Zhang, Y. and Zhang, M. (2010) Effect of Adiponectin Overexpression on Stability of Preexisting Plaques by Inducing Prolyl-4-Hydroxylase Expression. Circulation Journal, 74, 552-559.
https://doi.org/10.1253/circj.cj-09-0304
[23] Yang, X., Zhang, Y., Leng, X., Wang, Y., Gong, M., Liu, D., et al. (2025) Palmitoylated SARM1 Targeting P4HA1 Promotes Collagen Deposition and Myocardial Fibrosis: A New Target for Anti-Myocardial Fibrosis. Acta Pharmaceutica Sinica B, 15, 4789-4806.
https://doi.org/10.1016/j.apsb.2025.07.011
[24] 翁一玲, 李煌, 卓辰茜, 等. 基于UPLC-QE-MS技术的畅脉乐胶囊化学成分分析及其抗脑血栓的网络药理学研究[J]. 中国现代药物应用, 2022, 16(21): 173-178.
[25] 张宽, 罗柠, 叶华. 畅脉乐I号胶囊治疗动脉粥样硬化的网络药理学作用机制[J]. 医学诊断, 2022, 12(1): 27-37.
[26] 张宽, 欧余航, 罗春燕, 等. 畅脉乐胶囊(Ⅰ)质量评价[J]. 中成药, 2024, 46(7): 2134-2139.
[27] 黄松雄, 张玉琴, 刘巧婷, 等. 基于巨噬细胞自噬探讨畅脉乐胶囊对动脉粥样硬化大鼠斑块稳定性及凝血功能影响的机制[J]. 中国老年学杂志, 2024, 44(4): 871-876.
[28] 谢胜伟, 陈美华. 畅脉乐胶囊对颈动脉粥样硬化大鼠Wnt信号通路的影响[J]. 新中医, 2020, 52(21): 10-12.
[29] 苏天生, 陈梦婷, 谢峥桢, 等. 畅脉乐1号胶囊联合常规方法治疗气虚血瘀型急性冠脉综合征45例[J]. 福建中医药, 2024, 55(3): 1-3.
[30] 陈成, 张旺生, 陈铃, 等. 畅脉乐Ⅱ胶囊对血瘀型颈动脉粥样硬化患者CRP、IL-6及血栓相关参数的影响[J]. 山西中医, 2022, 38(5): 12-15.
[31] 陈美华, 谢胜伟. 益气活血化痰中药“畅脉乐胶囊”治疗颈动脉粥样硬化的临床研究[C]//中华中医药学会心病分会. 中华中医药学会心病分会全国第十二次学术年会暨中华中医药学会心病分会换届选举工作会议论文精选. 2010: 19-26.
[32] Liang, W.J., Zhou, S.N., Shan, M.R., Wang, X., Zhang, M., Chen, Y., et al. (2018) AMPKα Inactivation Destabilizes Atherosclerotic Plaque in Streptozotocin-Induced Diabetic Mice through AP-2α/miRNA-124 Axis. Journal of Molecular Medicine, 96, 403-412.
https://doi.org/10.1007/s00109-018-1627-8
[33] Wang, S.X., Zhang, C., Zhang, M., Liang, B., Zhu, H., Lee, J., et al. (2012) Activation of AMP-Activated Protein Kinase α2 by Nicotine Instigates Formation of Abdominal Aortic Aneurysms in Mice in Vivo. Nature Medicine, 18, 902-910.
https://doi.org/10.1038/nm.2711
[34] Li, H., Li, J., Jiang, X., Liu, S., Liu, Y., Chen, W., et al. (2019) Melatonin Enhances Atherosclerotic Plaque Stability by Inducing Prolyl-4-Hydroxylase α1 Expression. Journal of Hypertension, 37, 964-971.
https://doi.org/10.1097/hjh.0000000000001979
[35] 郑涛, 杨俊, 杨简, 等. 转录因子Sp1在心血管疾病中的作用[J]. 生命的化学, 2019, 39(3): 478-484.
[36] 沈建云, 朱茂英, 费路敏, 等. SP1被鉴定为miR-122-5p的一个转录因子[J]. 中华男科学杂志, 2021, 27(1): 11-16.
[37] 邵静, 蒋静. 基于AMPK/SIRT1通路探讨消溶稳斑方对不稳定斑块的作用[J]. 中国中医基础医学杂志, 2020, 26(12): 1779-1783.
[38] 姚昶, 高峰, 陈运, 等. 黄芪多糖胶原促进周围组织中血管新生与胶原合成的实验研究[J]. 中国修复重建外科杂志, 2011, 25(12): 1481-1485.
[39] 王南丁, 王文杰, 王新冰, 等. 芪丹通脉片对ApoE−/−小鼠动脉粥样硬化易损斑块TLR4/NF-κB信号转导通路的影响[J]. 中国中西医结合杂志, 2019, 39(08): 971-977.
[40] 章平衡, 李春燕, 刘永源, 等. 葛根素通过抑制ox-LDL诱导巨噬细胞焦亡通路活化稳定AS易损斑块[J]. 中国免疫学杂志, 2021, 37(18): 2212-2216.