Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China; National Clinical Research Center for Respiratory Diseases, Beijing, China.
Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Exp Cell Res. 2021 Jan 1;398(1):112392. doi: 10.1016/j.yexcr.2020.112392. Epub 2020 Nov 21.
The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated.
We compared serum PAI-2 levels between PAH patients and healthy controls, and examined the correlation between PAI-2 level and disease severity. In monocrotaline-induced PAH rats, we examined the effects of exogenous PAI-2 administration on pulmonary vascular remodeling and PAH development. The effect of PAI-2 and potential mechanisms was further examined in cultured hPASMCs.
The serum PAI-2 was decreased in PAH patients compared with controls. PAI-2 level was negatively correlated with mean pulmonary arterial pressure and estimated systolic pulmonary arterial pressure in ultrasonic cardiogram, while positively correlated with 6-min walking distance. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease in right ventricle systolic pressure, right ventricular hypertrophy index and percent media thickness of pulmonary arterioles. Further mechanistic investigation in hPASMCs showed that PAI-2 inhibited cell proliferation by preventing the activation of PI3K/Akt and ERK pathways.
PAI-2 is downregulated in PAH patients. PAI-2 attenuates PAH development by suppressing hPASMCs proliferation via the inhibition of PI3K/Akt and ERK pathways. PAI-2 may serve as a potential biomarker and therapeutic target for PAH.
肺血管平滑肌细胞（PASMCs）的增殖以及随后的肺血管重构导致肺动脉高压（PAH）。了解潜在的机制并确定可抑制 PASMC 增殖的分子对于开发有效的药物治疗至关重要。我们之前已经表明，纤溶酶原激活物抑制剂-2（PAI-2）可抑制人 PASMC（hPASMCs）的体外增殖。然而，其对 PAH 的抑制作用仍有待确定，其机制仍有待阐明。
我们比较了 PAH 患者和健康对照组之间的血清 PAI-2 水平，并研究了 PAI-2 水平与疾病严重程度之间的相关性。在野百合碱诱导的 PAH 大鼠中，我们研究了外源性 PAI-2 给药对肺血管重构和 PAH 发展的影响。进一步在培养的 hPASMCs 中研究了 PAI-2 的作用及其潜在机制。
与对照组相比，PAH 患者的血清 PAI-2 降低。PAI-2 水平与超声心动图中的平均肺动脉压和估计的收缩期肺动脉压呈负相关，而与 6 分钟步行距离呈正相关。在大鼠中，外源性 PAI-2 的给药显著逆转了野百合碱诱导的 PAH，表现为右心室收缩压、右心室肥厚指数和肺小动脉中层厚度百分比的降低。在 hPASMCs 中的进一步机制研究表明，PAI-2 通过阻止 PI3K/Akt 和 ERK 通路的激活来抑制细胞增殖。
PAI-2 在 PAH 患者中下调。PAI-2 通过抑制 PI3K/Akt 和 ERK 通路抑制 hPASMCs 增殖，从而减轻 PAH 的发展。PAI-2 可能作为 PAH 的潜在生物标志物和治疗靶点。
