Non-Muscle MLCK Contributes to Endothelial Cell Hyper-Proliferation through the ERK Pathway as a Mechanism for Vascular Remodeling in Pulmonary Hypertension.
Non-Muscle MLCK Contributes to Endothelial Cell Hyper-Proliferation through the ERK Pathway as a Mechanism for Vascular Remodeling in Pulmonary Hypertension.
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DOI：
10.3390/ijms232113641
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发表时间：
2022-11-07
影响因子：
5.6
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中科院分区：
文献类型：
--
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肺动脉高压（Pulmonary arterial hypertension， PAH）的特点是内皮功能障碍，肺动脉内皮细胞增殖和迁移不受控制，导致肺血管阻力增加，发病率高，生存率低。骨形态发生蛋白受体II （Bone morphogenetic protein receptor II, BMPR2）作为最常见的基因突变，在PAH的发病机制中起着重要作用。非肌肉肌球蛋白轻链激酶（nmMLCK）是细胞骨架的重要组成部分，最近的研究表明，nmMLCK活性的增加调节各种肺部疾病（如哮喘和急性肺损伤）的生物过程。在本研究中，我们旨在发现nmMLCK在肺动脉内皮细胞（HPAECs）增殖和迁移中的作用。我们使用了两种与PAH病理生物学相关的细胞模型，包括BMPR2沉默和血管内皮生长因子（VEGF）刺激的HPAECs。两种模型均显示nmMLCK活性增加，同时细胞增殖、炎症和细胞迁移显著增加。nmMLCK活性的上调也与ERK表达的增加有关，这表明潜在的整体细胞质相互作用。在机制上，我们证实当MLCK选择性抑制剂（ML-7）抑制nmMLCK时，增殖和迁移减弱。综上所述，我们的研究结果表明，nmMLCK上调与ERK表达增加相关，可能通过刺激细胞增殖和迁移参与了pah的发病机制。
Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction, uncontrolled proliferation and migration of pulmonary arterial endothelial cells leading to increased pulmonary vascular resistance resulting in great morbidity and poor survival. Bone morphogenetic protein receptor II (BMPR2) plays an important role in the pathogenesis of PAH as the most common genetic mutation. Non-muscle myosin light chain kinase (nmMLCK) is an essential component of the cellular cytoskeleton and recent studies have shown that increased nmMLCK activity regulates biological processes in various pulmonary diseases such as asthma and acute lung injury. In this study, we aimed to discover the role of nmMLCK in the proliferation and migration of pulmonary arterial endothelial cells (HPAECs) in the pathogenesis of PAH. We used two cellular models relevant to the pathobiology of PAH including BMPR2 silenced and vascular endothelial growth factor (VEGF) stimulated HPAECs. Both models demonstrated an increase in nmMLCK activity along with a robust increase in cellular proliferation, inflammation, and cellular migration. The upregulated nmMLCK activity was also associated with increased ERK expression pointing towards a potential integral cytoplasmic interaction. Mechanistically, we confirmed that when nmMLCK is inhibited by MLCK selective inhibitor (ML-7), proliferation and migration are attenuated. In conclusion, our results demonstrate that nmMLCK upregulation in association with increased ERK expression may contribute to the pathogenesis of PAHby stimulating cellular proliferation and migration.
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影响因子：
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