Superoxide-Mediated Upregulation of MMP9 Participates in BMPR2 Destabilization and Pulmonary Hypertension Development.
Superoxide-Mediated Upregulation of MMP9 Participates in BMPR2 Destabilization and Pulmonary Hypertension Development.
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DOI：
10.3390/antiox12111961
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发表时间：
2023-11-02
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--
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背景和目的：我们之前在类器官培养的牛肺动脉研究中报道，暴露于缺氧或内皮素-1的肺动脉高压（PH）条件导致骨形态发生蛋白受体2（BMPR2）功能的软骨寡聚基质蛋白（COMP）稳定性丧失，这是导致肺动脉高压发展的已知关键过程。根据随后的发现，这些情况与细胞外超氧化物介导的基质金属蛋白酶 9 (MMP-9) 表达增加有关。我们使用 MMP9 缺陷小鼠研究了这是否会导致 PH 发展。结果：暴露于 Sugen/Hypoxia (SuHx) 诱导 PH 的野生型 (WT) 小鼠肺部 MMP9 水平增加。 MMP9 敲除小鼠 (MMP9 KO) 的血流动力学测量表明，根据肺动脉压、右心室收缩压和富尔顿指数肥大测量的 ECHO 评估，与 WT 小鼠相比，它们的 PH 参数有所减弱。体外血管反应性研究表明，SuHx 小鼠肺动脉内皮依赖性和内皮非依赖性 NO 相关血管舒张反应受损，肺部 COMP 和 BMPR2 表达水平降低。这些变化在 MMP9 KO 小鼠中可能通过保留 BMPR2 的 COMP 依赖性稳定性而减弱。创新：这项研究支持超氧化物在增加 MMP9 方面的新功能以及与 BMPR2 相关的损伤在促进 PH 发展方面的作用，这可能成为未来治疗的目标。结论：超氧化物通过促进 MMP9 的增加，介导 BMPR2 耗竭及其对 PH 介质和 SuHx PH 小鼠模型的血管功能的控制。
Background and Aims: we previously reported in studies on organoid-cultured bovine pulmonary arteries that pulmonary hypertension (PH) conditions of exposure to hypoxia or endothelin-1 caused a loss of a cartilage oligomeric matrix protein (COMP) stabilization of bone morphogenetic protein receptor-2 (BMPR2) function, a known key process contributing to pulmonary hypertension development. Based on subsequent findings, these conditions were associated with an extracellular superoxide-mediated increase in matrix metalloproteinase 9 (MMP-9) expression. We investigated if this contributed to PH development using mice deficient in MMP9. Results: wild-type (WT) mice exposed to Sugen/Hypoxia (SuHx) to induce PH had increased levels of MMP9 in their lungs. Hemodynamic measures from MMP9 knockout mice (MMP9 KO) indicated they had attenuated PH parameters compared to WT mice based on an ECHO assessment of pulmonary artery pressure, right ventricular systolic pressure, and Fulton index hypertrophy measurements. In vitro vascular reactivity studies showed impaired endothelium-dependent and endothelium-independent NO-associated vasodilatory responses in the pulmonary arteries of SuHx mice and decreased lung levels of COMP and BMPR2 expression. These changes were attenuated in MMP9 KO mice potentially through preserving COMP-dependent stabilization of BMPR2. Innovation: this study supports a new function of superoxide in increasing MMP9 and the associated impairment of BMPR2 in promoting PH development which could be a target for future therapies. Conclusion: superoxide, through promoting increases in MMP9, mediates BMPR2 depletion and its consequent control of vascular function in response to PH mediators and the SuHx mouse model of PH.
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