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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model.
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A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model.

机译：缓激肽拮抗剂和半胱天冬酶抑制剂可预防大鼠模型中的严重肺动脉高压。

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Chronically hypoxic rats (exposed to 5000 m elevation for 3 weeks) develop pulmonary hypertension (PH) that is reversed upon return to normoxia and is blocked by bradykinin (BK) antagonist B9430 treatment (100 microg/kg s.c. three times per week). Treatment of rats with both the synthetic VEGF receptor-1/2 antagonist 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin-2-one (SU5416) (200 mg/kg, single s.c. injection) and hypoxia (3 weeks) causes irreversible severe PH characterized by marked elevation of pulmonary artery pressure (PAP), right ventricular hypertrophy, and obliteration of pulmonary arteries by proliferating endothelial cells (EC). Between weeks I and 2 of treatment, there is increased apoptotic EC death and caspase-3 activity. The combination of hypoxia with VEGFR-1 and -2 blockade appears to cause death of normal lung EC and proliferation of an apoptosis-resistant proliferating EC phenotype. Cotreatment with BK antagonist B9430 and (or) the broad caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp) (2 mg/kg three times per week) prevented development of severe PH and caused significant reduction of PAP: 39.7 +/- 4.6 mmHg in Z-Asp + SU5416, 37.1 +/- 1.2 mmHg in BK antagonist B9430 + SU5416, 27.2 +/- 0.7 mmHg in Z-Asp alone, and 36.6 +/- 3.0 mmHg in BK antagonist alone versus 48 +/- 1.7 mmHg in SU5416-treated rats and 32.8 +/-1.4 mmHg in vehicle-treated controls. The PAP correlated with the right ventricular mass. Pulmonary arteries of rats treated with Z-Asp and BK antagonist B9430 had a marked reduction of intravascular EC, yet there was still evidence of medial muscular hypertrophy, similar to that observed in chronically hypoxic rats not treated with SU5416. We conclude that EC death induced by VEGFR-2 blockade with SU5416 may trigger an EC selection process that allows for the expansion of apoptosis-resistant EC, possibly driven by mechanisms independent of VEGF and VEGFR-2.
机译：慢性低氧大鼠（暴露于海拔5000 m的地方持续3周）发展为肺动脉高压（PH），在恢复正常氧水平后会逆转，并被缓激肽（BK）拮抗剂B9430治疗（每周3次100 microg / kg s.c.）阻断。用合成的VEGF受体1/2拮抗剂3-[（（2,4-二甲基吡咯-5-基）亚甲基]吲哚-2-酮（SU5416）（200 mg / kg，单次sc注射）和缺氧（3周）会导致不可逆的严重PH，其特征为肺动脉压（PAP）明显升高，右心室肥大和内皮细胞增殖（EC）阻塞肺动脉。在治疗的第1周和第2周之间，凋亡性EC死亡和caspase-3活性增加。低氧与VEGFR-1和-2阻滞的结合似乎会导致正常肺EC的死亡和凋亡耐受性增殖EC表型的增殖。与BK拮抗剂B9430和（或）宽广的半胱天冬酶抑制剂Z-Asp-2,6-二氯苯甲酰氧基甲基酮（Z-Asp）（每周两次，每次3 mg / kg）共同治疗可防止严重PH的发生并导致PAP的显着降低：39.7 Z-Asp + SU5416中为+/- 4.6 mmHg，BK拮抗剂B9430 + SU5416中为37.1 +/- 1.2 mmHg，单独Z-Asp中为27.2 +/- 0.7 mmHg，单独BK拮抗剂为36.6 +/- 3.0 mmHg，而48在SU5416-处理的大鼠中为+/- 1.7 mmHg，在媒介物处理的对照组中为32.8 +/- 1.4 mmHg。 PAP与右室重量相关。用Z-Asp和BK拮抗剂B9430治疗的大鼠的肺动脉血管内EC明显降低，但仍存在内侧肌肥大的证据，类似于未用SU5416治疗的慢性低氧大鼠所观察到的。我们得出的结论是，用SU5416阻断VEGFR-2诱导的EC死亡可能触发EC选择过程，从而可能导致抗凋亡的EC扩展，这可能是由独立于VEGF和VEGFR-2的机制驱动的。

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