Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension
Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension
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DOI：
10.1152/physiolgenomics.00169.2007
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发表时间：
2008-04-22
影响因子：
4.6
通讯作者：
Garcia, Joe G. N.
中科院分区：
文献类型：
--
作者：
Moreno-Vinasco, Liliana;Gomberg-Maitland, Mardi;Garcia, Joe G. N.
肺动脉高压（PH）和癌症病理学共享生长因子和MAPK应激介导的信号传导途径，导致内皮和平滑肌细胞功能障碍和血管增生性血管病变。在这项研究中，我们评估了索拉非尼，一种血管生成中重要的多种激酶[VEGF受体（VEGFR）-1-3，PDGF受体（PDGFR）-β，Raf-1激酶]的抑制剂和抑制剂，作为一种潜在的PH治疗。使用了两种PH大鼠模型：常规缺氧诱导的PH模型和联合VEGFR-1和VEGFR-2双重抑制（SU-5416，单次20 mg/kg注射）和缺氧的增强PH模型。除常氧暴露对照动物外，4组动物均维持10%吸入O-2分数3.5周（缺氧/溶剂、缺氧/SU-5416、缺氧/索拉非尼和缺氧/SU-5416/索拉非尼）。与常氧对照动物相比，暴露于缺氧/SU-5416的大鼠出现了重度PH的血液动力学和组织学证据，而仅暴露于缺氧的大鼠仅显示血液动力学值（肺血管和右心室压力）轻度升高。索拉非尼治疗（每日灌胃，2.5 mg/kg）可预防血液动力学变化，并显示PH相关血管重塑显著减弱。与常氧对照大鼠相比，从缺氧[假发现率（FDR）6.5%]和缺氧/SU-5416（FDR 1.6%）激发大鼠获得的肺RNA表达谱（Affyphon平台）分别产生1，019和465个差异调节基因（倍数变化> 1.4）。通过实时RT-PCR或免疫印迹验证了一种新的分子标记，该分子标记由缺氧/SU-5416和缺氧/SU-5416/索拉非尼（FDR 6.7%）之间的38个差异表达基因组成。最后，免疫印迹研究证实了MAPK级联在两种PH模型中的上调，其被索拉非尼消除。总之，索拉非尼是一种治疗重度PH的新型潜在治疗方法，MAPK级联反应是一种潜在的典型靶点。
Pulmonary hypertension (PH) and cancer pathology share growth factor- and MAPK stress-mediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-beta, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxia-exposed control animals, four groups were maintained at 10% inspired O-2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]- and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change > 1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target.