Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability
Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability
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DOI：
10.1182/blood-2006-08-039438
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Gladwin, Mark T.
中科院分区：
文献类型：
--
作者：
Hsu, Lewis L.;Champion, Hunter C.;Gladwin, Mark T.
肺动脉高压是镰状细胞病的一种高度流行的并发症，也是早期死亡的一个强烈的危险因素。然而，导致肺血管病变的病理生理机制仍不清楚。转基因小鼠为动物模型中血管病理生理学的机制研究提供了机会。通过微心导管术，所有只表达人镰状血红蛋白的小鼠都出现了肺动脉高压，严重的肺和全身内皮功能障碍，以及血管不稳定，其特征是对真正的一氧化氮(NO)、NO供体和内皮依赖性血管扩张剂的反应减弱，对血管收缩药的反应增强。然而，镰刀鼠的非内皮依赖性血管扩张是正常的。镰刀鼠血管病变的机制与NO轴的全球失调有关：结构性一氧化氮合酶(NOS)活性受损，内皮型一氧化氮合酶(ENOS)二聚体丢失，血浆血红蛋白和超氧化物歧化清除NO增加，精氨酸酶活性增加，血管内亚硝酸盐储备枯竭。光镜和计算机断层扫描未发现丛状动脉重构或血栓/栓子。将镰状骨髓移植到野生型小鼠身上可以获得相同的表型，而在急性同种异体免疫溶血的非镰状小鼠模型中也观察到了相似的病理生物学。尽管在人类镰状细胞病中，溶血性贫血的时间比典型的肺动脉高压要短，但这些结果表明，溶血性贫血足以导致内皮功能障碍和NO的全球失调。
Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO.