Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages. Issue 10 (23rd October 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Circulation research. Volume 127:Issue 10(2020)
• Publication Date: 2020-10-23
• Subjects: macrophage -- niacin -- pulmonary arterial hypertension -- pulmonary artery remodeling; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.120.316784
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.