Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages
Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages
复制标题
烟酸通过巨噬细胞中的 H-PGDS 减轻肺动脉高压
DOI：
10.1161/circresaha.120.316784
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发表时间：
2020-10-23
影响因子：
20.1
通讯作者：
Shen, Yujun
中科院分区：
文献类型：
--
作者：
Jia, Daile;Bai, Peiyuan;Shen, Yujun
补充数字内容可在正文中找到。理论基础：肺动脉高压(PAH)的特征是进行性肺血管重塑，并伴有不同程度的血管周围炎症。烟酸是一种常用的降脂药物，通过促进前列腺素D2(PGD2)的释放而具有扩张血管和促进前列腺素D2(PGD2)释放的作用。然而，烟酸是否对PAH的发病机制具有保护作用仍不清楚。目的：本研究旨在确定烟酸是否能延缓PAH的发展，如果是的话，阐明其作用的分子机制。方法和结果：用血管内皮生长因子受体抑制剂SU5416和低氧暴露诱导大鼠肺动脉高压。我们发现烟酸可以减轻缺氧/SU5416诱导的小鼠肺动脉高压的发展，并通过减少肺动脉重塑来抑制野百合碱诱导的和缺氧/SU5416诱导的大鼠肺动脉高压的进展。烟酸主要通过H-PGDS(造血型PGD2合成酶)促进肺组织中PGD2的生成。H-PGDS的缺失，而不是Lipocalin型PGDS的缺失，加剧了低氧/SU5416诱导的小鼠PH，并取消了烟酸对PAH的保护作用。此外，H-PGDS主要表达于PH小鼠和特发性PAH患者肺组织中的巨噬细胞。巨噬细胞特异性H-PGDS缺失可显著减少肺组织中PGD2的生成，加重低氧/SU5416诱导的小鼠肺高压，并减弱烟酸对PAH的治疗作用。结论：烟酸治疗可通过刺激巨噬细胞释放H-PGDS来源的PGD2抑制血管重塑，从而改善PAH的进展。
Supplemental Digital Content is available in the text. Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, accompanied by varying degrees of perivascular inflammation. Niacin, a commonly used lipid-lowering drug, possesses vasodilating and proresolution effects by promoting the release of prostaglandin D2 (PGD2). However, whether or not niacin confers protection against PAH pathogenesis is still unknown. Objective: This study aimed to determine whether or not niacin attenuates the development of PAH and, if so, to elucidate the molecular mechanisms underlying its effects. Methods and Results: Vascular endothelial growth factor receptor inhibitor SU5416 and hypoxic exposure were used to induce pulmonary hypertension (PH) in rodents. We found that niacin attenuated the development of this hypoxia/SU5416–induced PH in mice and suppressed progression of monocrotaline-induced and hypoxia/SU5416–induced PH in rats through the reduction of pulmonary artery remodeling. Niacin boosted PGD2 generation in lung tissue, mainly through H-PGDS (hematopoietic PGD2 synthases). Deletion of H-PGDS, but not lipocalin-type PGDS, exacerbated the hypoxia/SU5416–induced PH in mice and abolished the protective effects of niacin against PAH. Moreover, H-PGDS was expressed dominantly in infiltrated macrophages in lungs of PH mice and patients with idiopathic PAH. Macrophage-specific deletion of H-PGDS markedly decreased PGD2 generation in lungs, aggravated hypoxia/SU5416–induced PH in mice, and attenuated the therapeutic effect of niacin on PAH. Conclusions: Niacin treatment ameliorates the progression of PAH through the suppression of vascular remodeling by stimulating H-PGDS–derived PGD2 release from macrophages.