Cyp2c44 gene disruption is associated with increased hematopoietic stem cells: implication in chronic hypoxia-induced pulmonary hypertension.
Cyp2c44 gene disruption is associated with increased hematopoietic stem cells: implication in chronic hypoxia-induced pulmonary hypertension.
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Cyp2c44 基因破坏与造血干细胞增加有关：对慢性缺氧诱导的肺动脉高压的影响。
DOI：
10.1152/ajpheart.00785.2016
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Gupte,SachinA
中科院分区：
文献类型：
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作者：
Hashimoto,Ryota;Joshi,SachindraRaj;Jiang,Houli;Capdevila,JorgeH;McMurtry,IvanF;LaniadoSchwartzman,Michal;Gupte,SachinA
我们最近证明，小鼠细胞色素 P-450 2c44 基因 (Cyp2c44) 的破坏会加剧小鼠慢性缺氧诱导的肺动脉重塑和高血压。随后，我们偶然发现Cyp2c44基因破坏也会增加骨髓和血液中的造血干细胞（HSC）数量。因此，本研究的目的是研究 CYP2C44 衍生的类二十烷酸是否调节 HSC 增殖/细胞生长，以及增加的 HSC 是否有助于 Cyp2c44 敲除小鼠中慢性缺氧诱导的肺动脉重塑。我们的研究结果表明，缺乏 CYP2C44 环氧化酶（催化花生四烯酸氧化为环氧二十碳三烯酸 (EET) 和羟基二十碳四烯酸 (HETE)）会增加 1) HSC（CD34+、CD117+ 和 CD133+）、2) 促血管生成（CD34+CD133+ 和与野生型小鼠相比，骨髓和血液中的 CD34+CD117+CD133+) 细胞和 3) 免疫原性/炎症（CD34+CD11b+、CD133+CD11b+、F4/80+、CD11b+ 和 F4/80+CD11b+）巨噬细胞。在各种 CYP2C44 衍生的花生四烯酸中，只有 15-HETE 在应用于骨髓细胞培养时减少了 CD117+ 细胞数量。有趣的是，来自促血管生成干细胞的CD133+和冯维勒布兰德因子阳性细胞在暴露于慢性缺氧的小鼠的骨髓、血液和肺中以及在CYP2C44缺陷小鼠的重塑和闭塞的肺动脉中增加。总之，我们的结果表明，CYP2C44 衍生的 15-HETE 在下调 HSC 增殖和生长中发挥着关键作用，因为 Cyp2c44 基因的破坏增加了 HSC，这可能有助于慢性缺氧诱导的肺动脉重塑和闭塞。新的和值得注意的这项研究表明，细胞色素 P-450 2C44 在控制造血干细胞的表型和当这种酶被敲除时，干细胞就会分化。这些干细胞产生增加的循环单核细胞和巨噬细胞，并导致慢性缺氧诱导的肺动脉重塑和高血压的发病机制。
We have recently demonstrated that disruption of the murine cytochromeP-450 2c44 gene (Cyp2c44)exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found thatCyp2c44gene disruption also increases hematopoietic stem cell (HSC) numbers in bone marrow and blood. Therefore, the objective of the present study was to investigate whether CYP2C44-derived eicosanoids regulate HSC proliferation/cell growth and whether increased HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries inCyp2c44knockout mice. Our findings demonstrated that lack of CYP2C44 epoxygenase, which catalyzed the oxidation of arachidonic acid to epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic (HETE) acids, increases the numbers of1) HSCs (CD34+, CD117+, and CD133+),2) proangiogenic (CD34+CD133+and CD34+CD117+CD133+) cells, and3) immunogenic/inflammatory (CD34+CD11b+, CD133+CD11b+, F4/80+, CD11b+, and F4/80+CD11b+) macrophages in bone marrow and blood compared with wild-type mice. Among the various CYP2C44-derived arachidonic acids, only 15-HETE decreased CD117+cell numbers when applied to bone marrow cell cultures. Interestingly, CD133+and von Willebrand factor-positive cells, which are derived from proangiogenic stem cells, are increased in the bone marrow, blood, and lungs of mice exposed to chronic hypoxia and in remodeled and occluded pulmonary arteries of CYP2C44-deficient mice. In conclusion, our results demonstrate that CYP2C44-derived 15-HETE plays a critical role in downregulating HSC proliferation and growth, because disruption of theCyp2c44gene increased HSCs that potentially contribute to chronic hypoxia-induced pulmonary arterial remodeling and occlusion.NEW & NOTEWORTHYThis study demonstrates that cytochromeP-450 2C44 plays a critical role in controlling the phenotype of hematopoietic stem cells and that when this enzyme is knocked out, stem cells are differentiated. These stem cells give rise to increased circulating monocytes and macrophages and contribute to the pathogenesis of chronic hypoxia-induced pulmonary artery remodeling and hypertension.