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 pro-resolution 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 (HySu) -induced PH in mice and suppressed progression of monocrotaline- and HySu -induced PH in rats through the reduction of pulmonary artery remodeling. Niacin boosted PGD2 generation in lung tissue, mainly through hematopoietic PGD2 synthases (H-PGDS). Deletion of H-PGDS, but not lipocalin-type PGDS, exacerbated the HySu -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 idiopathic PAH patients. Macrophage-specific deletion of H-PGDS markedly decreased PGD2 generation in lungs, aggravated HySu -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.

Keywords: Hematopoietic prostaglandin D synthase; macrophage; niacin; prostaglandin D2; pulmonary artery remodeling.