SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling.
SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling.
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DOI：
10.1177/20458940211021528
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发表时间：
2021-07
影响因子：
2.6
通讯作者：
Zisman LS
中科院分区：
文献类型：
--
作者：
Sitapara R;Sugarragchaa C;Zisman LS
SU5416加慢性缺氧导致大鼠肺动脉高压，并假定通过VEGFR2抑制发生。卡博替尼是一种比SU5416更有效的VEGFR2抑制剂。因此，我们假设卡博替尼加缺氧将在大鼠中诱导严重的肺动脉高压。进行细胞增殖和药代动力学研究。大鼠皮下或通过渗透泵给予SU5416或卡博替尼，并保持缺氧三周。右心室收缩压和肥大在第14和28天后，从缺氧去除进行了评价。右心室纤维化采用苦天狼星红染色。进行SU5416和卡博替尼的激酶组抑制谱。测定SU5416和卡博替尼对BMPR 2的抑制剂结合常数，并进行肺mRNA的Nanostring分析。卡博替尼是比SU5416更有效的VEGFR抑制剂，并且在大鼠中具有更长的半衰期。卡博替尼皮下注射加缺氧不诱导严重的肺动脉高压。缺氧后14和28天的右心室收缩压分别为36.8 ± 2.3 mmHg和36.2 ± 3.4 mmHg，而正常对照组为27.5 ± 1.5 mmHg。对于在缺氧期间通过渗透泵给予的卡博替尼，右心室收缩压在缺氧后14天时为40.0 ± 3.1 mmHg，在缺氧后28天时为27.9 ± 1.9 mmHg。SU5416+低氧诱导了严重的肺动脉高压（低氧后14和28天右心室收缩压分别为61.9 ± 6.1 mmHg和64.9 ± 8.4 mmHg）。与SU5416相比，卡博替尼在缺氧后14天诱导较少的右心室肥大（右心室游离壁重量/（左心室游离壁重量+室间隔重量）。与卡博替尼组相比，SU 5416组中的右心室纤维化更广泛。SU5416（但不是卡博替尼）抑制BMPR2。Nanostring分析显示，在缺氧后28天组中，SU5416对肺BMP 10和VEGFR1的基因表达有影响。总之，使用卡博替尼加缺氧的选择性VEGFR2抑制不会诱导严重的肺动脉高压。由SU5416加缺氧引起的重度肺动脉高压可能是由于VEGFR2和BMPR2联合抑制所致。
SU5416 plus chronic hypoxia causes pulmonary arterial hypertension in rats and is assumed to occur through VEGFR2 inhibition. Cabozantinib is a far more potent VEGFR2 inhibitor than SU5416. Therefore, we hypothesized that cabozantinib plus hypoxia would induce severe pulmonary arterial hypertension in rats. Cell proliferation and pharmacokinetic studies were performed. Rats were given SU5416 or cabozantinib subcutaneously or via osmotic pump and kept hypoxic for three weeks. Right ventricular systolic pressure and hypertrophy were evaluated at days 14 and 28 following removal from hypoxia. Right ventricular fibrosis was evaluated with Picro-Sirius Red staining. Kinome inhibition profiles of SU5416 and cabozantinib were performed. Inhibitor binding constants of SU5416 and cabozantinib for BMPR2 were determined and Nanostring analyses of lung mRNA were performed. Cabozantinib was a more potent VEGFR inhibitor than SU5416 and had a longer half-life in rats. Cabozantinib subcutaneous plus hypoxia did not induce severe pulmonary arterial hypertension. Right ventricular systolic pressure at 14 and 28 days post-hypoxia was 36.8 ± 2.3 mmHg and 36.2 ± 3.4 mmHg, respectively, versus 27.5 ± 1.5 mmHg in normal controls. For cabozantinib given by osmotic pump during hypoxia, right ventricular systolic pressure was 40.0 ± 3.1 mmHg at 14 days and 27.9 ± 1.9 mmHg at 28 days post-hypoxia. SU5416 plus hypoxia induced severe pulmonary arterial hypertension (right ventricular systolic pressure 61.9 ± 6.1 mmHg and 64.9 ± 8.4 mmHg at 14 and 28 days post-hypoxia, respectively). Cabozantinib induced less right ventricular hypertrophy (right ventricular free wall weight/(left ventricular free wall weight + interventricular septum weight) at 14 days post-hypoxia compared to SU5416. Right ventricular fibrosis was more extensive in the SU5416 groups compared to the cabozantinib groups. SU5416 (but not cabozantinib) inhibited BMPR2. Nanostring analyses showed effects on pulmonary gene expression of BMP10 and VEGFR1 in the SU5416 28 days post-hypoxia group. In conclusion, selective VEGFR2 inhibition using cabozantinib plus hypoxia did not induce severe pulmonary arterial hypertension. Severe pulmonary arterial hypertension due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.
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影响因子：
2.6
作者：
Nicolls MR;Mizuno S;Taraseviciene-Stewart L;Farkas L;Drake JI;Al Husseini A;Gomez-Arroyo JG;Voelkel NF;Bogaard HJ
通讯作者：
Bogaard HJ
DOI：
10.4137/cmo.s10594
发表时间：
2013-10-29
期刊：
Clinical Medicine Insights. Oncology
影响因子：
--
作者：
Gross-Goupil M;François L;Quivy A;Ravaud A
通讯作者：
Ravaud A
影响因子：
4.8
作者：
Taraseviciene-Stewart, L;Kasahara, Y;Tuder, RM
通讯作者：
Tuder, RM
影响因子：
5.6
作者：
Milling RV;Grimm D;Krüger M;Grosse J;Kopp S;Bauer J;Infanger M;Wehland M
通讯作者：
Wehland M
影响因子：
4
作者：
Upton, Paul D.;Park, John E. S.;Morrell, Nicholas W.
通讯作者：
Morrell, Nicholas W.