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首页> 外文期刊>Pulmonary Circulation >Hypoxic Pulmonary Hypertension in Mice with Constitutively Active Platelet-Derived Growth Factor Receptor-β:
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Hypoxic Pulmonary Hypertension in Mice with Constitutively Active Platelet-Derived Growth Factor Receptor-β:

机译：组成性活性血小板衍生生长因子受体-β的小鼠低氧性肺动脉高压：

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Platelet-derived growth factor (PDGF) has been implicated in the pathobiology of vascular remodeling. The multikinase inhibitor imatinib that targets PDGF receptor (PDGFR), c-kit and Abl kinases, shows therapeutic efficacy against experimental pulmonary hypertension (PH); however, the role of PDGFR-β in experimental PH has not been examined by genetic approach. We investigated the chronic hypoxia-induced PH in mice carrying an activating point mutation of PDGFR-β (D849N) and evaluated the therapeutic efficacy of imatinib. In addition, we studied pulmonary global gene expression and confirmed the expression of identified genes by immunohistochemistry. Chronically hypoxic D849N mice developed PH and strong pulmonary vascular remodeling that was improved by imatinib (100 mg/kg/day) as evident from the significantly reduced right ventricular systolic pressure, right ventricular hypertrophy and muscularization of peripheral pulmonary arteries. Global gene expression analysis revealed that stromal cell derived factor SDF)-1αwas significantly upregulated, which was confirmed by immunohistochemistry. Moreover, an enhanced immunoreactivity for SDF-1α, PDGFR-β and CXCR4, the receptor for SDF-1α was localized to the α-smooth muscle cell (SMC) actin positive pulmonary vascular cells in hypoxic mice and patients with idiopathic pulmonary arterial hypertension (IPAH). In conclusion, our findings substantiate the major role of PDGFR activation in pulmonary vascular remodeling by a genetic approach. Immunohistochemistry findings suggest a role for SDF-1α/CXCR4 axis in pulmonary vascular remodeling and point to a potential interaction between the chemokine SDF-1 and the growth factor PDGF signaling. Future studies designed to elucidate an interaction between the chemokine SDF-1 and the PDGF system may uncover novel therapeutic targets.
机译：血小板衍生的生长因子（PDGF）与血管重塑的病理生物学有关。靶向PDGF受体（PDGFR），c-kit和Abl激酶的多激酶抑制剂伊马替尼显示出对实验性肺动脉高压（PH）的治疗功效;然而，PDGFR-β在实验性PH中的作用尚未通过遗传方法进行检验。我们调查了携带PDGFR-β（D849N）激活点突变的小鼠中的慢性低氧诱导的PH，并评估了伊马替尼的治疗效果。此外，我们研究了肺整体基因表达并通过免疫组织化学证实了已鉴定基因的表达。慢性低氧D849N小鼠出现PH和强烈的肺血管重构，伊马替尼（100 mg / kg / day）改善了肺血管重构，这从右室收缩压明显降低，右室肥大和周围肺动脉肌肉化明显可见。整体基因表达分析表明，基质细胞衍生因子SDF）-1α显着上调，这已通过免疫组织化学证实。此外，缺氧小鼠和特发性肺动脉高压患者中SDF-1α，PDGFR-β和CXCR4（SDF-1α的受体）的免疫反应性增强了，其定位于α-平滑肌细胞（SMC）肌动蛋白阳性肺血管细胞（ IPAH）。总之，我们的发现通过遗传方法证实了PDGFR激活在肺血管重构中的主要作用。免疫组织化学结果表明，SDF-1α/ CXCR4轴在肺血管重塑中发挥作用，并指出趋化因子SDF-1与生长因子PDGF信号传导之间可能存在相互作用。旨在阐明趋化因子SDF-1与PDGF系统之间相互作用的未来研究可能会发现新的治疗靶标。

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