Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling
Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling
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DOI：
10.1161/circulationaha.108.779751
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发表时间：
2008-11-11
期刊：
影响因子：
37.8
通讯作者：
Schaefer, Stefan
中科院分区：
文献类型：
--
作者：
Klein, Martina;Schermuly, Ralph T.;Schaefer, Stefan
背景 - 抑制酪氨酸激酶，包括血小板衍生生长因子受体，可以降低实验和临床肺动脉高压的肺动脉压。我们假设，除了抑制酪氨酸激酶外，抑制丝氨酸/苏氨酸激酶 Raf-1（也称为 c-Raf）和 b-Raf 还可有效控制肺动脉高压中的肺血管和右心重塑。 方法和结果 - 我们研究了新型多激酶抑制剂索拉非尼（与酪氨酸激酶伊马替尼相比）的效果，索拉非尼可抑制酪氨酸激酶以及丝氨酸/苏氨酸激酶抑制剂，对血流动力学、肺和右心室（RV）重塑以及实验性肺动脉高压的下游信号传导有影响。野百合碱注射后 14 天，雄性大鼠再口服索拉非尼（每天 10 毫克/公斤）、伊马替尼（每天 50 毫克/公斤）或载体（每组 n = 12 至 16）14 天。与安慰剂相比（82.9 +/- 6.0 mm Hg），索拉非尼使 RV 收缩压降低至 35.0 +/- 1.5 mm Hg，伊马替尼降低至 54.0 +/- 4.4 mm Hg。与此同时，索拉非尼和伊马替尼均减少了右心室肥厚和肺动脉肌化。索拉非尼对右心室收缩压和右心室质量的影响明显大于伊马替尼。索拉非尼可阻止 Raf-1 的磷酸化，并抑制 RV 心肌和肺部下游 ERK1/2 信号通路的激活。此外，索拉非尼而非伊马替尼可以拮抗加压素诱导的心肌细胞系 H9c2 肥大。结论 - 多激酶抑制剂索拉非尼可预防实验性肺动脉高压中的肺重构并改善心肺功能。索拉非尼发挥直接的心肌抗肥厚作用，这似乎是通过抑制 Raf 激酶途径介导的。酪氨酸和丝氨酸/苏氨酸激酶的联合抑制可能为治疗肺动脉高压和相关的右心重塑提供一种选择。 （流通。2008 年；118：2081-2090。）
Background - Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce pulmonary arterial pressure in experimental and clinical pulmonary hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls pulmonary vascular and right heart remodeling in pulmonary hypertension.Methods and Results - We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, pulmonary and right ventricular (RV) remodeling, and downstream signaling in experimental pulmonary hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (n = 12 to 16 per group). RV systolic pressure was decreased to 35.0 +/- 1.5 mm Hg by sorafenib and to 54.0 +/- 4.4 mm Hg by imatinib compared with placebo (82.9 +/- 6.0 mm Hg). In parallel, both sorafenib and imatinib reduced RV hypertrophy and pulmonary arterial muscularization. The effects of sorafenib on RV systolic pressure and RV mass were significantly greater than those of imatinib. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of the downstream ERK1/ 2 signaling pathway in RV myocardium and the lungs. In addition, sorafenib but not imatinib antagonized vasopressin-induced hypertrophy of the cardiomyoblast cell line H9c2.Conclusions - The multikinase inhibitor sorafenib prevents pulmonary remodeling and improves cardiac and pulmonary function in experimental pulmonary hypertension. Sorafenib exerts direct myocardial antihypertrophic effects, which appear to be mediated via inhibition of the Raf kinase pathway. The combined inhibition of tyrosine and serine/threonine kinases may provide an option to treat pulmonary arterial hypertension and associated right heart remodeling. (Circulation. 2008; 118: 2081-2090.)