Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice
Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice
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DOI：
10.1161/circulationaha.104.492488
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发表时间：
2005-07-26
期刊：
影响因子：
37.8
通讯作者：
Zhang, YY
中科院分区：
文献类型：
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作者：
Song, YL;Jones, JE;Zhang, YY
背景-骨形态发生蛋白受体-2(BMPR2)杂合突变(BMPR2(+/-))小鼠具有与某些特发性肺动脉高压(IPAH)患者相似的遗传特征。为了了解BMPR2(+/-)小鼠在IPAH发生发展中的作用，我们研究了BMPR2(+/-)小鼠的表型和对炎症应激的反应。方法和结果-BMPR2(+/-)小鼠在非应激条件下具有与野生型小鼠相同的寿命、右室收缩压(RVSP)和肺组织学改变。然而，当用表达5-脂氧合酶(Ad5LO)的重组腺病毒治疗时，BMPR2(+/-)小鼠的RVSP显著高于野生型小鼠。RVSP升高出现在Ad5LO注射后的前2周。在Ad5LO治疗4周后，BMPR2(+/-)小鼠的远端肺小动脉出现了适度但显著的肌化。尿中血管活性分子代谢产物的测定显示，在5LO转基因表达过程中，BMPR2(+/-)和野生型小鼠的半胱氨酰白三烯、前列环素代谢物和前列腺素E(2)均有类似程度的增加，而尿内皮素-1仍未被检测到。相反，BMPR2(+/-)组的尿血栓素A(2)代谢物显著高于野生型小鼠，并与RVSP的增加平行。BMPR2(+/-)小鼠的血小板活化标志物、5-羟色胺和可溶性P-选择素有高于野生型小鼠的趋势。细胞培养研究发现，BMP处理降低了IL-1β刺激的肺上皮细胞株A549中血栓烷A(2)的产生。结论BMPR2(+/-)小鼠不会自发性地发生肺动脉高压，但在炎症应激下，它们比野生型小鼠更容易发生RVSP增加、血栓素A(2)产生和血管重塑。
Background - Bone morphogenetic protein receptor-2 (BMPR2)-heterozygous, mutant (BMPR2(+/-)) mice have a genetic trait similar to that of certain patients with idiopathic pulmonary arterial hypertension (IPAH). To understand the role of BMPR2 in the development of IPAH, we examined the phenotype of BMPR2(+/-) mice and their response to inflammatory stress.Methods and Results - BMPR2(+/-) mice were found to have the same life span, right ventricular systolic pressure (RVSP), and lung histology as those of wild-type mice under unstressed conditions. However, when treated with recombinant adenovirus expressing 5-lipoxygenase (Ad5LO), BMPR2(+/-) mice exhibited significantly higher RVSP than wild-type mice. The increase of RVSP occurred in the first 2 weeks after Ad5LO delivery. Modest but significant muscularization of distal pulmonary arterioles appeared in BMPR2(+/-) mice 4 weeks after Ad5LO treatment. Measurement of urinary metabolites of vasoactive molecules showed that cysteinyl leukotrienes, prostacyclin metabolites, and PGE(2) were all increased to a similar degree in both BMPR2(+/-) and wild-type mice during 5LO transgene expression, whereas urinary endothelin-1 remained undetectable. Urinary thromboxane A(2) metabolites, in contrast, were significantly higher in BMPR2(+/-) than in wild-type mice and paralleled the increase in RVSP. Platelet activation markers, serotonin, and soluble P-selectin showed a trend toward higher concentrations in BMPR2(+/-) than wild-type mice. Cell culture studies found that BMP treatment reduced interleukin-1 beta-stimulated thromboxane A(2) production in the pulmonary epithelial cell line A549.Conclusions - BMPR2(+/-) mice do not develop pulmonary hypertension spontaneously; however, under inflammatory stress, they are more susceptible to an increase in RVSP, thromboxane A(2) production, and vascular remodeling than wild-type mice.