钙调结合蛋白对血流相关性肺动脉高压肺血管重构的保护作用。
Protective effects of calcyclin-binding protein against pulmonary vascular remodeling in flow-associated pulmonary arterial hypertension.
机构信息
Echocardiography Medical Center, Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Department of Laboratory Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
出版信息
Respir Res. 2022 Aug 30;23(1):223. doi: 10.1186/s12931-022-02137-z.
BACKGROUND
Pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) is recognized as a cancer-like disease with a proliferative and pro-migratory phenotype in pulmonary artery smooth muscle cells (PASMCs). Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) has been implicated in the progression of various cancers; however, it has not been previously studied in the context of CHD-PAH. Here, we aimed to examine the function of CacyBP/SIP in CHD-PAH and explore its potential as a novel regulatory target for the disease.
METHODS
The expression of CacyBP/SIP in PASMCs was evaluated both in the pulmonary arterioles of patients with CHD-PAH and in high-flow-induced PAH rats. The effects of CacyBP/SIP on pulmonary vascular remodeling and PASMC phenotypic switch, proliferation, and migration were investigated. LY294002 (MedChemExpress, NJ, USA) was used to block the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway to explore changes in PASMC dysfunction induced by low CacyBP/SIP levels. Hemodynamics and pulmonary arterial remodeling were further explored in rats after short-interfering RNA-mediated decrease of CacyBP/SIP expression.
RESULTS
CacyBP/SIP expression was markedly reduced both in the remodeled pulmonary arterioles of patients with CHD-PAH and in high-flow-induced PAH rats. Low CacyBP/SIP expression promoted hPASMC phenotypic switch, proliferation, and migration via PI3K/AKT pathway activation. Our results indicated that CacyBP/SIP protected against pulmonary vascular remodeling through amelioration of hPASMC dysfunction in CHD-PAH. Moreover, after inhibition of CacyBP/SIP expression in vivo, we observed increased right ventricular hypertrophy index, poor hemodynamics, and severe vascular remodeling.
CONCLUSIONS
CacyBP/SIP regulates hPASMC dysfunction, and its increased expression may ameliorate progression of CHD-PAH.
背景
与先天性心脏病（CHD）相关的肺动脉高压（PAH）被认为是一种类似于癌症的疾病，在肺动脉平滑肌细胞（PASMCs）中具有增殖和促迁移表型。钙调蛋白结合蛋白/Siah-1 相互作用蛋白（CacyBP/SIP）已被牵涉到各种癌症的进展中；然而，它在 CHD-PAH 的背景下尚未得到研究。在这里，我们旨在研究 CacyBP/SIP 在 CHD-PAH 中的功能，并探讨其作为该疾病新的调节靶点的潜力。
方法
评估了 CacyBP/SIP 在 CHD-PAH 患者的肺小动脉和高流量诱导的 PAH 大鼠中的 PASMCs 中的表达。研究了 CacyBP/SIP 对肺血管重构和 PASMC 表型转换、增殖和迁移的影响。使用 LY294002（MedChemExpress，NJ，USA）阻断磷脂酰肌醇 3-激酶/蛋白激酶 B（PI3K/AKT）通路，以研究低 CacyBP/SIP 水平诱导的 PASMC 功能障碍的变化。在 CacyBP/SIP 表达降低的大鼠中进一步研究了短干扰 RNA 介导的 CacyBP/SIP 表达降低后的血流动力学和肺动脉重构。
结果
CacyBP/SIP 的表达在 CHD-PAH 患者的重构肺小动脉和高流量诱导的 PAH 大鼠中均显著降低。低 CacyBP/SIP 表达通过激活 PI3K/AKT 通路促进 hPASMC 表型转换、增殖和迁移。我们的结果表明，CacyBP/SIP 通过改善 CHD-PAH 中的 hPASMC 功能障碍来防止肺血管重构。此外，体内抑制 CacyBP/SIP 表达后，我们观察到右心室肥厚指数增加、血流动力学不佳和严重的血管重构。
结论
CacyBP/SIP 调节 hPASMC 功能障碍，其表达增加可能改善 CHD-PAH 的进展。
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