Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages.

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.

• Authors: Daile Jia, Peiyuan Bai, Naifu Wan, Jiao Liu, Qian Zhu, Yuhu He, Guilin Chen, Jing Wang, Han Chen, Chen Wang, Ankang Lyu, Michael Lazarus, Yunchao Su, Yoshihiro Urade, Ying Yu, Jian Zhang, Yujun Shen
• Journal: Circulation research (Circ Res) Vol. 127 Issue 10 Pg. 1323-1336 (10 23 2020) ISSN: 1524-4571 [Electronic] United States
• PMID: 32912104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Hypolipidemic Agents
• Niacin
• Intramolecular Oxidoreductases
• HPGDS protein, human
• Prostaglandin D2

Topics

• Animals
• Antihypertensive Agents (pharmacology, therapeutic use)
• Cells, Cultured
• Humans
• Hypertension, Pulmonary (drug therapy, metabolism)
• Hypolipidemic Agents (pharmacology, therapeutic use)
• Intramolecular Oxidoreductases (genetics, metabolism)
• Lung (drug effects, metabolism)
• Macrophages (drug effects, metabolism)
• Mice
• Niacin (pharmacology, therapeutic use)
• Prostaglandin D2 (metabolism)
• Pulmonary Artery (drug effects, metabolism)
• Rats