Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin αvβ3FAK/AKT Pathway Suppression
Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin αvβ3FAK/AKT Pathway Suppression
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DOI：
10.1161/circgenetics.116.001591
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发表时间：
2017-01-01
影响因子：
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通讯作者：
Lu, Ankang
中科院分区：
文献类型：
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作者：
Jia, Daile;Zhu, Qian;Lu, Ankang
背景-肺动脉重构以血管平滑肌增生增加为特征，常见于危及生命的肺动脉高压（PAH）。临床研究表明骨保护素血清水平与PAH严重程度之间存在相关性。在此，我们的目的是研究血管骨保护素的表达及其对肺动脉平滑肌细胞增殖的影响，方法和结果PAH患者血清骨保护素水平显著升高，并与疾病严重程度相关，如世界卫生组织（WHO）功能分类和6-分钟步行距离测试同样，在缺氧加SU 5416和野百合碱诱导的PAH动物模型的肺动脉中观察到骨保护素表达增加。此外，骨保护素破坏通过减少肺血管重构减弱缺氧加SU 5416诱导的PAH进展，而慢病毒骨保护素重建通过增加肺动脉平滑肌细胞增殖加剧PAH。此外，通路分析表明，骨保护素诱导肺动脉平滑肌细胞增殖与整合素α（V）β（3），引发下游的粘着斑激酶和AKT pathway activation. Conclusions骨保护素促进PAH的发病机制，通过调节肺动脉平滑肌细胞增殖，这表明它可能是一个潜在的生物标志物和治疗靶点在这种疾病。
Background-Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to investigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity.Methods and Results-Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin alpha(v)beta(3) to elicit downstream focal adhesion kinase and AKT pathway activation.Conclusions-Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.