Journal
CIRCULATION RESEARCH
Volume 127, Issue 10, Pages 1323-1336Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.120.316784
Keywords
macrophage; niacin; pulmonary arterial hypertension; pulmonary artery remodeling
Funding
- National Key R&D Program of China [2018YFA0800601, 2017YFC1307404, 2017YFC1307402]
- National Natural Science Foundation of China [81790623, 81525004, 91439204, 31771269, 81970540, 81771513]
- Natural Science Foundation of Tianjin [17JCYB-JC40700, 18JCYBJC27300, 17JCYBJC26800]
- Japan Society for the Promotion of Science (JSPS) [16H01881]
- Young Elite Scientists Sponsorship Program by Tianjin [TJSQNTJ-2018-10]
- Grants-in-Aid for Scientific Research [16H01881] Funding Source: KAKEN
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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 D-2 (PGD(2)). 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 PGD(2) generation in lung tissue, mainly through H-PGDS (hematopoietic PGD(2) 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 PGD(2) 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 PGD(2) release from macrophages.
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