先天性心脏病相关肺动脉高压的代谢重编程 机制与精准医疗新策略
Metabolic Reprogramming Mechanisms and Precision Medicine Strategies for Pulmonary Arterial Hypertension Associated with Congenital Heart Disease
DOI: 10.12677/acm.2026.162582, PDF,   
作者: 温雪姣：赣南医科大学第一临床医学院，江西 赣州；肖根发*：赣南医科大学第一附属医院心脏医学中心，江西 赣州
关键词: 先天性心脏病；肺动脉高压；代谢重编程；免疫代谢；多组学；精准医疗；Congenital Heart Disease； Pulmonary Arterial Hypertension； Metabolic Reprogramming； Immune Metabolism； Multi-Omics； Precision Medicine
摘要: 先天性心脏病相关肺动脉高压(PAH-CHD)的发病机制已超越传统血流动力学模型，转变为以代谢重编程为核心的复杂网络疾病。本综述系统阐述代谢重编程作为整合遗传易感性、血流动力学应激和免疫炎症反应的核心枢纽，驱动肺血管重塑的分子机制。重点论述糖酵解、谷氨酰胺代谢、线粒体功能障碍及脂代谢异常等关键代谢通路的改变如何通过影响细胞能量供应、生物合成及表观遗传调控，主动促进疾病进展。并进一步总结了基于代谢组学的生物标志物发现、代谢–免疫交互作用的最新证据，以及多组学整合在解析疾病异质性中的应用。最后，展望了靶向代谢通路的新型治疗策略及迈向精准医疗的具体路径，旨在为PAH-CHD的机制研究与临床防治提供全新视角。
Abstract: The pathogenesis of congenital heart disease-associated pulmonary arterial hypertension (PAH-CHD) has moved beyond the traditional hemodynamic model, evolving into a complex network disease centered on metabolic reprogramming. This review systematically elaborates on the molecular mechanisms by which metabolic reprogramming acts as a core hub integrating genetic susceptibility, hemodynamic stress, and immune-inflammatory responses to drive pulmonary vascular remodeling. It focuses on how alterations in key metabolic pathways—including glycolysis, glutamine metabolism, mitochondrial dysfunction, and lipid metabolism disorders—actively promote disease progression by affecting cellular energy supply, biosynthesis, and epigenetic regulation. Furthermore, this paper summarizes the discovery of metabolomics-based biomarkers, the latest evidence of metabolism-immune crosstalk, and the application of multi-omics integration in deciphering disease heterogeneity. Finally, it proposes novel therapeutic strategies targeting metabolic pathways and specific approaches toward precision medicine, aiming to provide a brand-new perspective for the mechanistic research, clinical prevention, and treatment of PAH-CHD.
文章引用：温雪姣, 肖根发. 先天性心脏病相关肺动脉高压的代谢重编程 机制与精准医疗新策略[J]. 临床医学进展, 2026, 16(2): 1877-1883. https://doi.org/10.12677/acm.2026.162582

参考文献

[1] 中华医学会呼吸病学分会肺栓塞与肺血管病学组, 中国医师协会呼吸医师分会肺栓塞与肺血管病工作委员会, 全国肺栓塞与肺血管病防治协作组, 等. 中国肺动脉高压诊断与治疗指南(2021版) [J]. 中华医学杂志, 2021, 101(1): 11-51.
[2] Humbert, M., Kovacs, G., Hoeper, M.M., Badagliacca, R., Berger, R.M.F., Brida, M., et al. (2022) 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: Developed by the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on Rare Respiratory Diseases (ERN-LUNG). European Heart Journal, 43, 3618-3731. [Google Scholar] [CrossRef] [PubMed]
[3] 刘明波, 何新叶, 杨晓红, 等. 《中国心血管健康与疾病报告2023》要点解读[J]. 中国心血管杂志, 2024, 29(4): 305-324.
[4] Rabinovitch, M. (2012) Molecular Pathogenesis of Pulmonary Arterial Hypertension. Journal of Clinical Investigation, 122, 4306-4313. [Google Scholar] [CrossRef] [PubMed]
[5] Sutendra, G. and Michelakis, E.D. (2014) The Metabolic Basis of Pulmonary Arterial Hypertension. Cell Metabolism, 19, 558-573. [Google Scholar] [CrossRef] [PubMed]
[6] 罗勤, 柳志红, 奚群英, 等. 中国动脉型肺动脉高压患者生存现状调查[J]. 中国循环杂志, 2022, 37(11): 1111-1115.
[7] 常开丽, 刘演龙, 李昇铃, 等. 先天性心脏病相关性肺动脉高压[J]. 实用心脑肺血管病杂志, 2024, 32(1): 1-8.
[8] 罗海云, 林子英. 机械敏感性通道Piezo1上调参与高剪切力诱导的肺动脉高压[J]. 中华结核和呼吸杂志, 2023, 46(1): 26.
[9] Yan, Y., He, Y., Chen, J., Fu, Y., Liu, S., Hua, L., et al. (2021) Plasma Metabolomics in Perioperative Period of Defect Repair in Patients with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease. European Heart Journal, 42, ehab724.1868. [Google Scholar] [CrossRef] 
[10] Evans, J.D.W., Girerd, B., Montani, D., Wang, X., Galiè, N., Austin, E.D., et al. (2016) BMPR2 Mutations and Survival in Pulmonary Arterial Hypertension: An Individual Participant Data Meta-Analysis. The Lancet Respiratory Medicine, 4, 129-137. [Google Scholar] [CrossRef] [PubMed]
[11] Zhu, N., Swietlik, E.M., Welch, C.L., Pauciulo, M.W., Hagen, J.J., Zhou, X., et al. (2021) Rare Variant Analysis of 4241 Pulmonary Arterial Hypertension Cases from an International Consortium Implicates FBLN2, PDGFD, and Rare De Novo Variants in Pah. Genome Medicine, 13, Article No. 80. [Google Scholar] [CrossRef] [PubMed]
[12] Morrell, N.W., Aldred, M.A., Chung, W.K., Elliott, C.G., Nichols, W.C., Soubrier, F., et al. (2019) Genetics and Genomics of Pulmonary Arterial Hypertension. European Respiratory Journal, 53, Article ID: 1801899. [Google Scholar] [CrossRef] [PubMed]
[13] Saygin, D., Tabib, T., Bittar, H.E.T., Valenzi, E., Sembrat, J., Chan, S.Y., et al. (2020) Transcriptional Profiling of Lung Cell Populations in Idiopathic Pulmonary Arterial Hypertension. Pulmonary Circulation, 10, 1-15. [Google Scholar] [CrossRef] [PubMed]
[14] Zhang, R.Y., Liu, J., Sun, Y., et al. (2022) [Metabolic Reprogramming in Pulmonary Hypertension]. Chinese Journal of Tuberculosis and Respiratory Diseases, 45, 313-317.
[15] Kazmirczak, F., Vogel, N.T., Prisco, S.Z., Patterson, M.T., Annis, J., Moon, R.T., et al. (2024) Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension. Circulation Research, 135, 1067-1083. [Google Scholar] [CrossRef] [PubMed]
[16] Cai, Z., Tu, L., Tian, S., Deng, L., Fu, Y., Phan, C., et al. (2025) IDO‐1 Promotes Pulmonary Vascular Remodeling via Kynurenine Pathway in Pulmonary Arterial Hypertension. Journal of the American Heart Association, 14, e040896. [Google Scholar] [CrossRef] [PubMed]
[17] Chaturvedi, G., Dubey, N., Panchbhai, P., Singh, S., Singh, R., Baitha, U., et al. (2026) Mitochondrial-ER Crosstalk: An Emerging Mechanism in the Pathophysiology of Pulmonary Arterial Hypertension. Mitochondrion, 86, Article D: 102094. [Google Scholar] [CrossRef] 
[18] Li, Y., Zhang, Y., Han, B., Xue, L., Wei, Y. and Li, G. (2024) Single-Cell Sequencing Analysis Confirms the Association of ANRIL with the Increased Smooth Muscle Cell Proliferation and Migration Gene Signatures in Pulmonary Artery Hypertension in Silico. Advances in Medical Sciences, 69, 217-223. [Google Scholar] [CrossRef] [PubMed]
[19] Bermes, D.G. (2022) Role of Lactate Transporters in Pulmonary Hypertension. Ph.D. Thesis, Justus-Liebig-Universität Gießen.
[20] Duan, Q., Zhang, S., Wang, Y., Lu, D., Sun, Y. and Wu, Y. (2022) Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk, Immunosuppression and Anti-Apoptosis to Clinical Applications. Frontiers in Cell and Developmental Biology, 10, Article 1069555. [Google Scholar] [CrossRef] [PubMed]
[21] DeBerardinis, R.J. and Keshari, K.R. (2022) Metabolic Analysis as a Driver for Discovery, Diagnosis, and Therapy. Cell, 185, 2678-2689. [Google Scholar] [CrossRef] [PubMed]
[22] Chen, C., Luo, F., Wu, P., Huang, Y., Das, A., Chen, S., et al. (2020) Metabolomics Reveals Metabolite Changes of Patients with Pulmonary Arterial Hypertension in China. Journal of Cellular and Molecular Medicine, 24, 2484-2496. [Google Scholar] [CrossRef] [PubMed]
[23] Xu, B., Huang, C., Zhang, C., Lin, D. and Wu, W. (2022) NMR-Based Metabolomic Analysis of Plasma in Patients with Adult Congenital Heart Disease and Associated Pulmonary Arterial Hypertension: A Pilot Study. Metabolites, 12, Article 845. [Google Scholar] [CrossRef] [PubMed]
[24] He, Y., Yan, Y., Chen, J., Liu, S., Hua, L., Jiang, X., et al. (2021) Plasma Metabolomics in the Perioperative Period of Defect Repair in Patients with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease. Acta Pharmacologica Sinica, 43, 1710-1720. [Google Scholar] [CrossRef] [PubMed]
[25] Tomaszewski, M., Styczeń, A., Krysa, M., Michalski, A., Morawska-Michalska, I., Hymos, A., et al. (2024) Lymphocyte Involvement in the Pathology of Pulmonary Arterial Hypertension. International Journal of Molecular Sciences, 25, Article 13455. [Google Scholar] [CrossRef] [PubMed]
[26] Legchenko, E., Chouvarine, P., Hysko, K., Qadri, F., Wesolowski, R., Specker, E., et al. (2025) Inhalation of the Novel Tryptophan Hydroxylase 1 Inhibitor TPT-004 Alleviates Pulmonary Arterial Hypertension. American Journal of Respiratory Cell and Molecular Biology, 73, 288-298. [Google Scholar] [CrossRef] [PubMed]
[27] Yuan, C., Chen, H., Hou, H., Wang, J., Yang, Q. and He, G. (2020) Protein Biomarkers and Risk Scores in Pulmonary Arterial Hypertension Associated with Ventricular Septal Defect: Integration of Multi-Omics and Validation. American Journal of Physiology-Lung Cellular and Molecular Physiology, 319, L810-L822. [Google Scholar] [CrossRef] [PubMed]
[28] 李菲菲, 黄钰钦, 陈若霞, 等. 肺动脉高压相关线粒体自噬生物标志物及其作用的分析与验证[J]. 广西医科大学学报, 2024, 41(3): 419-429.
[29] Rada-Pascual, K.M., Zúniga-Muñoz, A.M., Alvarez-Alvarez, Y.Q., Del Valle-Mondragón, L., Rubio-Gayosso, I., Martínez-Olivares, C.E., et al. (2025) Fenofibrate as a Modulator of the Renin-Angiotensin System in Su/Hx-Induced Pulmonary Arterial Hypertension. International Journal of Molecular Sciences, 26, Article 10251. [Google Scholar] [CrossRef] 
[30] Noh, M., Mitra, A., Krebes, L., Schmitz, W., Dudek, J., Agarwal, S., et al. (2025) C-Type Natriuretic Peptide Attenuates Enhanced Glycolysis and De Novo Pyrimidine Synthesis in Pericytes of Patients with Pulmonary Arterial Hypertension. Communications Biology, 8, Article No. 1199. [Google Scholar] [CrossRef] [PubMed]
[31] Humbert, M., McLaughlin, V., Gibbs, J.S.R., Gomberg-Maitland, M., Hoeper, M.M., Preston, I.R., et al. (2021) Sotatercept for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine, 384, 1204-1215. [Google Scholar] [CrossRef] [PubMed]
[32] Saleh, K.M., Mallat, J., Mohammed, S., Bodi, G., Alazazzi, H., Salim, S., et al. (2025) Comparative Efficacy and Safety of Prostacyclin Therapies for Pulmonary Arterial Hypertension: A Systematic Review and Network Meta-Analysis. Frontiers in Medicine, 12, Article 1643220. [Google Scholar] [CrossRef] 
[33] Luna-Lopez, R., Segura de la Cal, T., Sarnago Cebada, F., Martin de Miguel, I., Hinojosa, W., Cruz-Utrilla, A., et al. (2023) Triple Vasodilator Therapy in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease. Heart, 110, 346-352. [Google Scholar] [CrossRef] [PubMed]
[34] Smith, M.A., Guardado, E.S., Boehme, J., Datar, S.A., Maltepe, E., Swami, N., et al. (2025) Microvascular Preservation and Cardiomyocyte Hyperplasia Underlie Adaptive Right Ventricle Development in Congenital Heart Disease-Pulmonary Arterial Hypertension. American Journal of Physiology-Heart and Circulatory Physiology, 329, H907-H919. [Google Scholar] [CrossRef] 
[35] Neijenhuis, R.M.L., MacDonald, S.T., Zemrak, F., Mertens, B.J.A., Dinsdale, A., Hunter, A., et al. (2024) Effect of Sodium-Glucose Cotransporter 2 Inhibitors in Adults with Congenital Heart Disease. Journal of the American College of Cardiology, 83, 1403-1414. [Google Scholar] [CrossRef] [PubMed]

为你推荐