Periostin-expressing cell-specific transforming growth factor-β inhibition in pulmonary artery prevents pulmonary arterial hypertension

Transforming growth factor beta (TGF-β) has been shown to play a critical role in pathogenesis of pulmonary arterial hypertension (PAH) although the precise role of TGF-β signaling remains uncertain. A recent report has shown that periostin (Pn) is one of the most upregulated proteins in human PAH lung compared with healthy lungs. We established type I TGF-β receptor knockout mice specifically with Pn expressing cell (Pn-Cre/Tgfb1fl/fl mice). Increases in PA pressure and pulmonary artery muscularization were induced by hypoxia of 10% oxygen for 4 weeks. Lung Pn expression was markedly induced by 4 week-hypoxia. Pn-Cre/Tgfb1fl/fl mice showed lower right ventricular pressure elevation, inhibition of PA medial thickening. Fluorescent co-immunostaining showed that Smad3 activation in Pn expressing cell is attenuated. These results suggest that TGF-β signaling in Pn expressing cell may have an important role in the pathogenesis of PAH by controlling medial thickening.转化生长因子β（Transforming growth factor beta, TGF-β）已被证实于肺动脉高压（pulmonary arterial hypertension, PAH）的发病机制中发挥关键作用，尽管TGF-β信号通路的确切功能仍未明确。近期一项研究显示，相较于健康肺组织，骨膜蛋白（periostin, Pn）是人类PAH肺组织中上调幅度最高的蛋白之一。本研究构建了特异性在骨膜蛋白表达细胞中敲除TGF-βⅠ型受体的小鼠（Pn-Cre/Tgfb1fl/fl小鼠）。将小鼠置于10%氧浓度的低氧环境中培养4周，可诱导其肺动脉压力升高及肺动脉肌化。4周低氧可显著诱导肺组织中骨膜蛋白的表达。Pn-Cre/Tgfb1fl/fl小鼠的右心室压力升高幅度更低，且肺动脉中膜增厚受到抑制。荧光双免疫染色结果显示，骨膜蛋白表达细胞中的Smad3激活受到削弱。上述结果表明，骨膜蛋白表达细胞中的TGF-β信号通路可能通过调控肺血管中膜增厚，参与PAH的发病过程。