Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages

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 prosta...

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Published in:	Circulation research 2020-10, Vol.127 (10), p.1323-1336
Main Authors:	Jia, Daile, Bai, Peiyuan, Wan, Naifu, Liu, Jiao, Zhu, Qian, He, Yuhu, Chen, Guilin, Wang, Jing, Chen, Han, Wang, Chen, Lyu, Ankang, Lazarus, Michael, Su, Yunchao, Urade, Yoshihiro, Yu, Ying, Zhang, Jian, Shen, Yujun
Format:	Article
Language:	eng
Subjects:	Animals Antihypertensive Agents - pharmacology Antihypertensive Agents - therapeutic use Cells, Cultured Humans Hypertension, Pulmonary - drug therapy Hypertension, Pulmonary - metabolism Hypolipidemic Agents - pharmacology Hypolipidemic Agents - therapeutic use Intramolecular Oxidoreductases - genetics Intramolecular Oxidoreductases - metabolism Lung - drug effects Lung - metabolism Macrophages - drug effects Macrophages - metabolism Mice Niacin - pharmacology Niacin - therapeutic use Prostaglandin D2 - metabolism Pulmonary Artery - drug effects Pulmonary Artery - metabolism Rats
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Summary:	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.
ISSN:	0009-7330 1524-4571