maresin-1 通过激活 ALXR/HSP90α 轴改善线粒体稳态来防治肺动脉高压。
Maresin-1 protects against pulmonary arterial hypertension by improving mitochondrial homeostasis through ALXR/HSP90α axis.
机构信息
Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
Division of Pulmonary Vascular Disease, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
出版信息
J Mol Cell Cardiol. 2023 Aug;181:15-30. doi: 10.1016/j.yjmcc.2023.05.005. Epub 2023 May 25.
AIMS
Pulmonary arterial hypertension (PAH) is a progressive and lethal disease characterized by continuous proliferation of pulmonary arterial smooth muscle cell (PASMCs) and increased pulmonary vascular remodeling. Maresin-1 (MaR1) is a member of pro-resolving lipid mediators and exhibits protective effects on various inflammation-related diseases. Here we aimed to study the role of MaR1 in the development and progression of PAH and to explore the underlying mechanisms.
METHODS AND RESULTS
We evaluated the effect of MaR1 treatment on PAH in both monocrotaline (MCT)-induced rat and hypoxia+SU5416 (HySu)-induced mouse models of pulmonary hypertension (PH). Plasma samples were collected from patients with PAH and rodent PH models to examine MaR1 production. Specific shRNA adenovirus or inhibitors were used to block the function of MaR1 receptors. The data showed that MaR1 significantly prevented the development and blunted the progression of PH in rodents. Blockade of the function of MaR1 receptor ALXR, but not LGR6 or RORα, with BOC-2, abolished the protective effect of MaR1 against PAH development and reduced its therapeutic potential. Mechanistically, we demonstrated that the MaR1/ALXR axis suppressed hypoxia-induced PASMCs proliferation and alleviated pulmonary vascular remodeling by inhibiting mitochondrial accumulation of heat shock protein 90α (HSP90α) and restoring mitophagy.
CONCLUSION
MaR1 protects against PAH by improving mitochondrial homeostasis through ALXR/HSP90α axis and represents a promising target for PAH prevention and treatment.
目的
肺动脉高压（PAH）是一种进行性和致命性疾病，其特征为肺动脉平滑肌细胞（PASMCs）持续增殖和肺血管重构增加。maresin-1（MaR1）是促解决脂质介质的成员，对各种与炎症相关的疾病具有保护作用。在此，我们旨在研究 MaR1 在 PAH 的发生和进展中的作用，并探讨其潜在机制。
方法和结果
我们评估了 MaR1 治疗对 MCT 诱导的大鼠和缺氧+SU5416（HySu）诱导的肺动脉高压（PH）小鼠模型中 PAH 的影响。收集来自 PAH 患者和啮齿动物 PH 模型的血浆样本，以检测 MaR1 的产生。使用特异性 shRNA 腺病毒或抑制剂阻断 MaR1 受体的功能。结果表明，MaR1 显著预防了 PH 的发生，并减弱了 PH 的进展。用 BOC-2 阻断 MaR1 受体 ALXR 的功能，但不阻断 LGR6 或 RORα，可消除 MaR1 对 PAH 发生的保护作用并降低其治疗潜力。在机制上，我们证明 MaR1/ALXR 轴通过抑制热休克蛋白 90α（HSP90α）的线粒体积累和恢复线粒体自噬，抑制低氧诱导的 PASMCs 增殖并减轻肺血管重构，从而起到保护作用。
结论
MaR1 通过 ALXR/HSP90α 轴改善线粒体动态平衡来预防 PAH，这代表了一种有前途的 PAH 预防和治疗靶点。
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