5-Lipoxagenase deficiency attenuates L-NAME-induced hypertension and vascular remodeling
5-Lipoxagenase deficiency attenuates L-NAME-induced hypertension and vascular remodeling
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5-脂氧酶缺乏可减弱 L-NAME 诱导的高血压和血管重塑
DOI：
10.1016/j.bbadis.2019.05.021
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发表时间：
2019-09-01
影响因子：
6.2
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Chen, Jia-xiang;Xue, Kun-yue;Jiang, Wei
背景：L-精氨酸-一氧化氮通路的阻断可导致高血压。5-脂氧合酶（5-LO）是参与白三烯（LT）合成的关键酶。然而，一氧化氮合酶功能障碍是否通过调节5-LO活性及其下游炎性代谢产物诱导高血压血管重塑仍然未知。在野生型（WT）和5-LO敲除（5-LO KO）小鼠中，6周L-NAME治疗显著诱导高血压和血管重塑，5-LO KO小鼠尾动脉和颈动脉血压低于L-NAME暴露的WT小鼠。在组织学上，L-NAME诱导更少的中膜厚度，中膜-管腔比，胶原沉积和更少的Ki-67阳性血管平滑肌细胞（VSMCs），但更多的弹性蛋白表达在胸部和肠系膜动脉瘤的5-LO KO比L-NAME治疗的WT小鼠。L-NAME显著增加WT小鼠血浆和中性粒细胞培养上清液中LT含量，包括LTB 4和半胱氨酰LT（CysLTs）。在免疫组化上，L-NAME促进5-LO和5-LO激活蛋白在培养的中性粒细胞核膜上的共定位，这伴随着培养上清液中LT含量的升高。此外，LTs还能显著促进VSMCs的BrdU掺入、迁移和表型改变。L-NAME可能激活免疫细胞（如中性粒细胞）中的5-LO/LT通路，并促进5-LO代谢产物（包括LTB 4和CysLT）的生成，这些产物加重高血压的血管重塑。5-LO缺乏可通过降低5-LO下游炎症代谢产物的水平来防止高血压和血管重塑。
Background: Abnormalities of the L-arginine-nitric oxide pathway induce hypertension. 5-Lipoxygenase (5-LO) is the key enzyme involved in synthesis of leukotrienes (LTs). However, whether nitricoxide synthase dysfunction induces hypertensive vascular remodeling by regulating 5-LO activity and its downstream inflammatory metabolites remains unknown.Methods and results: Six-week L-NAME treatment significantly induced hypertension and vascular remodeling in both wild-type (WT) and 5-LO knockout (5-LO KO) mice, and blood pressure in caudal and carotid arteries was lower in 5-LO KO than WT mice with L-NAME exposure. On histology, L-NAME induced less media thickness, media-to-lumen ratio, and collagen deposition and fewer Ki-67 positive vascular smooth muscle cells (VSMCs) but more elastin expression in thoracic and mesenteric aortas of 5-LO KO than L-NAME treated WT mice. L-NAME significantly increased LT content, including LTB4 and cysteinyl LT (CysLTs), in plasma and neutrophil culture supernatants from WT mice. On immunohistochemistry, L-NAME promoted the colocalization of 5-LO and 5-LO activating protein on the nuclear envelope of cultured neutrophils, which was accompanied by elevated LT content in culture supernatants. In addition, LTs significantly promoted BrdU incorporation, migration and phenotypic modulation in VSMCs.Conclusion. L-NAME may activate the 5-LO/LT pathway in immune cells, such as neutrophils, and promote the products of 5-LO metabolites, including LTB4 and CysLTs, which aggravate vascular remodeling in hypertension. 5-LO deficiency may protect against hypertension and vascular remodeling by reducing levels of 5-LO downstream inflammatory metabolites.