Nox4-ROS-TRPM2通路对慢性低氧肺动脉高压中PASMCs增殖、迁移和凋亡的调控
摘要：慢性低氧肺动脉高压（CH-PH）是一种严重的疾病，其发病机制尚不完全清楚。过氧化氢酶4（Nox4）-氧自由基（ROS）-瞬时受体电位离子通道M2（TRPM2）通路在细胞增殖、迁移和凋亡中发挥重要作用，但其在CH-PH中的作用尚未明确。本研究利用平滑肌细胞（PASMCs）细胞株和CH-PH动物模型，探讨了Nox4-ROS-TRPM2通路对PASMCs增殖、迁移和凋亡的调控作用。结果表明，低氧刺激可显著促进PASMCs增殖、迁移和凋亡，同时增加Nox4、ROS和TRPM2的表达水平。使用Nox4抑制剂（GKT137831）和TRPM2抑制剂（ACA）可明显抑制低氧诱导PASMCs增殖和迁移，同时促进其凋亡。此外，实验证明ROS通过TRPM2通路调节了低氧诱导的PASMCs凋亡。在CH-PH动物模型中，GKT137831和ACA可显著改善肺动脉压力，降低右心室肥厚指数。综上所述，Nox4-ROS-TRPM2通路在CH-PH中发挥了重要作用，其抑制可能有望成为CH-PH的潜在策略。
关键词：慢性低氧肺动脉高压；Nox4；ROS；TRPM2；PASMCs；增殖；迁移；凋亡；策略
Abstract: Chronic hypoxia pulmonary hypertension (CH-PH) is a serious disease with uncle
ar pathogenesis. The NADPH oxidase 4 (Nox4)-reactive oxygen species (ROS)-transient receptor potential melastatin 2 (TRPM2) pathway plays an important role in cell proliferation, migration and apoptosis, but its role in CH-PH remains unclear. In this study, using smooth muscle cell (PASMCs) cell lines and CH-PH animal models, we investigated the regulation of Nox4-ROS-TRPM2 pathway on PASMCs proliferation, migration and apoptosis. The results showed that hypoxia stimulation significantly promoted PASMCs proliferation, migration and apoptosis, while increasing the expression levels of Nox4, ROS and TRPM2. The use of Nox4 inhibitor (GKT137831) and TRPM2 inhibitor (ACA) significantly inhibited hypoxia-induced PASMCs proliferation and migration, while promoting its apoptosis. In addition, the experimental results proved that ROS regulated hypoxia-induced PASMCs apoptosis through the TRPM2 pathway. In the CH-PH animal model, GKT137831 and ACA treatments significantly improved pulmonary arterial pressure and reduced right ventricular hypertrophy index. In conclusion, Nox4-ROS-TRPM2 pathway plays an important role in CH-PH, and its inhibition may become a potential therapeutic strategy for CH-PH.
Keywords: chronic hypoxia pulmonary hypertension; Nox4; ROS; TRPM2; PASMCs; proliferation; migration; apoptosis; therapeutic strateg
Chronic hypoxia pulmonary hypertension (CH-PH) is a progressive disease associated with high morbidity and mortality rates. It is characterized by sustained pulmonary vasoconstriction and remodeling, resulting in increased pulmonary vascular resistance, pulmonary arterial pressure, and right ventricular hypertrophy. The pathogenesis of CH-PH is complex and multifactorial, involving the interaction of various cellular and molecular pathways. One such pathway involves the role of reactive oxygen species (ROS) and its downstream effectors, including transient receptor potential melastatin 2 (TRPM2) ion channel.
Studies have shown that ROS generated by NADPH oxidase 4 (Nox4) are involved in the pathogenesis of CH-PH. Nox4-mediated ROS production is elevated in pulmonary artery smooth muscle cells (PASMCs) in response to chronic hypoxia. ROS can activate various signaling pathways, such as the MAPK pathway, leading to increased PASMCs proliferatio
n and migration, and decreased apoptosis. Moreover, ROS can activate TRPM2, a calcium-permeable ion channel, which can modulate various cellular processes, including cell death, inflammation, and migration. Activation of TRPM2 channels in PASMCs can promote intracellular calcium influx, leading to increased pulmonary vasoconstriction and pulmonary arterial remodeling.
Inhibition of the Nox4-ROS-TRPM2 pathway has emerged as a promising therapeutic strategy for CH-PH. Small molecule inhibitors, such as GKT137831, can selectively inhibit Nox4 and reduce ROS production, leading to decreased PASMCs proliferation, migration, and apoptosis. Additionally, TRPM2 channel blockers, such as ACA, can inhibit calcium influx, leading to reduced pulmonary vasoconstriction and remodeling. In animal models of CH-PH, treatment with GKT137831 and ACA has been shown to reduce pulmonary arterial pressure and right ventricular hypertrophy index.
In conclusion, the Nox4-ROS-TRPM2 pathway plays a critical role in the pathogenesis of CH-PH. Inhibition of this pathway with small molecule inhibitors, such as GKT137831 and T
RPM2 channel blockers, may offer a promising therapeutic strategy for CH-PH. Further studies are needed to elucidate the precise mechanisms involved in the Nox4-ROS-TRPM2 pathway and to evaluate the safety and efficacy of these therapeutic agents in clinical settings
reactive oxygen species (ros)Furthermore, it is important to note that CH-PH is associated with significant clinical morbidity and mortality. Patients with CH-PH often experience dyspnea, fatigue, and reduced exercise capacity, and may eventually develop right heart failure. Therefore, early diagnosis and effective management are crucial for improving patient outcomes.
Current treatment options for CH-PH include medications such as endothelin-receptor antagonists, phosphodiesterase inhibitors, and prostacyclin analogues, as well as surgical interventions such as atrial septostomy and lung transplantation. However, these treatments are often limited by their side effects or invasiveness, and there is a need for safer and more effective therapies.
The identification of the Nox4-ROS-TRPM2 pathway as a key mediator of CH-PH pathogen
esis opens up new avenues for therapeutic intervention. Small molecule inhibitors such as GKT137831 and TRPM2 channel blockers have shown promise in preclinical studies and may represent a novel approach to treating CH-PH.
However, further studies are needed to fully understand the precise mechanisms involved in this pathway and to evaluate the safety and efficacy of these therapies in clinical settings. It will also be important to identify biomarkers or imaging modalities that can be used to monitor disease progression and response to therapy in patients with CH-PH.
Overall, the identification of the Nox4-ROS-TRPM2 pathway as a therapeutic target in CH-PH represents an important advance in our understanding of this complex disease. Continued research in this area has the potential to improve the lives of patients with CH-PH and may lead to the development of new and effective treatments
Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by elevated pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart failure and premature death. Chronic hypoxia (CH) is a common risk factor for th
e development of PH, which can occur in chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep apnea, and high-altitude settings.

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