State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease-Chinese Academy of Medical Sciences Peking Union Medical College, Beijing, China.
Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
FASEB J. 2019 Jun;33(6):7236-7251. doi: 10.1096/fj.201802121RR. Epub 2019 Mar 20.
Recent studies indicated that osteopontin (OPN) was involved in the genesis and progression of pulmonary arterial hypertension (PAH); however, its role in congenital heart disease-associated PAH (CHD/PAH) remains unknown. Our results showed that OPN was increased in lungs and plasma of patients with Eisenmenger syndrome; moreover, OPN and αβ-integrin expression levels were augmented in rat lungs exposed to systemic-to-pulmonary shunt. Cell culture assay demonstrated that distal pulmonary arterial smooth muscle cells (PASMCs) from rat lungs suffering from volume and pressure overload exhibited enhanced proliferation compared with those from healthy rats. Mechanical stretch (20% at 1 Hz) increased OPN expression and activated ERK1/2 and protein kinase B (Akt) signal pathway in distal PASMCs from healthy rats. Interestingly, OPN enhanced the proliferation and migration of PASMCs while blocking αβ-integrin with neutralizing antibody LM609 or Arg-Gly-Asp peptidomimetic antagonist cyclo(Ala-Arg-Gly-Asp-3-aminomethylbenzoyl) (XJ735), rectified the proliferative and migratory effects of OPN, which were partially mediated ERK1/2 and Akt signaling pathways. Furthermore, surgical correction of systemic-to-pulmonary shunt, particularly XJ735 supplementation after surgical correction of systemic-to-pulmonary shunt, significantly alleviated the pulmonary hypertensive status in terms of pulmonary hemodynamic indices, pulmonary vasculopathy, and right ventricular hypertrophy. In summary, OPN alteration in lungs exposed to systemic-to-pulmonary shunt exerts a deteriorative role in pulmonary vascular remodeling through modulating the proliferation and migration of PASMCs, at least in part, ανβ3-ERK1/2 and ανβ3-Akt signaling pathways. Antagonizing OPN receptor ανβ3-integrin accelerated the regression of pulmonary vasculopathy after surgical correction of systemic-to-pulmonary shunt, indicating a potential therapeutic strategy for patients with CHD/PAH.-Meng, L., Liu, X., Teng, X., Gu, H., Yuan, W., Meng, J., Li, J., Zheng, Z., Wei, Y., Hu, S. Osteopontin plays important roles in pulmonary arterial hypertension induced by systemic-to-pulmonary shunt.
最近的研究表明，骨桥蛋白（OPN）参与了肺动脉高压（PAH）的发生和进展；然而，其在先天性心脏病相关肺动脉高压（CHD/PAH）中的作用尚不清楚。我们的研究结果表明，Eisenmenger 综合征患者的肺部和血浆中 OPN 增加；此外，在体肺分流大鼠的肺部中，OPN 和 αβ-整合素的表达水平增加。细胞培养实验表明，与健康大鼠相比，来自容量和压力超负荷大鼠肺部的远端肺动脉平滑肌细胞（PASMCs）表现出增强的增殖。机械拉伸（1 Hz 时为 20%）增加了健康大鼠远端 PASMCs 中 OPN 的表达，并激活了 ERK1/2 和蛋白激酶 B（Akt）信号通路。有趣的是，OPN 增强了 PASMCs 的增殖和迁移，而用中和抗体 LM609 或 Arg-Gly-Asp 肽模拟物拮抗剂 XJ735 阻断 αβ-整合素则纠正了 OPN 的增殖和迁移作用，该作用部分由 ERK1/2 和 Akt 信号通路介导。此外，体肺分流的手术矫正，特别是体肺分流矫正后的 XJ735 补充，在肺血流动力学指标、肺血管病变和右心室肥厚方面显著减轻了肺动脉高压状态。总之，体肺分流暴露的肺部中 OPN 的改变通过调节 PASMCs 的增殖和迁移，至少部分通过 ανβ3-ERK1/2 和 ανβ3-Akt 信号通路，在肺血管重塑中发挥恶化作用。拮抗 OPN 受体 ανβ3-整合素加速了体肺分流手术后肺血管病变的消退，表明这为 CHD/PAH 患者提供了一种潜在的治疗策略。-孟，L.，刘，X.，滕，X.，顾，H.，袁，W.，孟，J.，李，J.，郑，Z.，魏，Y.，胡，S. 骨桥蛋白在体肺分流引起的肺动脉高压中发挥重要作用。
