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Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages

Originally published11 Sep 2020https://doi.org/10.1161/CIRCRESAHA.120.316784Circulation Research. 2020;127:1323–1336

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.

Footnotes

*D.J., P.B., N.W., J.L. and Y.S., J.Z., Y.Y. contributed equally to this article.

The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.120.316784.

For Sources of Funding and Disclosures, see page 1334.

Correspondence to: Yujun Shen, PhD, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Rd, Heping District, Tianjin 300070, China, Email
Jian Zhang, PhD, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Rd, Heping District, Tianjin 300070, China, Email

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Novelty and Significance

What Is Known?

  • Pulmonary vascular remodeling is the main pathological hallmark of pulmonary arterial hypertension contributing to the detrimental effects of this disease.

  • Vascular inflammation mediated by perivascular inflammatory cells such as macrophages and T cells is an important driver for pulmonary vascular remodeling.

  • Niacin exhibits anti-inflammatory and vasodilating effects by releasing prostaglandin D2.

What New Information Does This Article Contribute?

  • Niacin ameliorates experimental pulmonary hypertension) in rodents through the suppression of pulmonary artery remodeling.

  • Niacin boosts prostaglandin D2 generation in lung tissue mainly through H-PGDS (hematopoietic PGD2 synthases) in macrophages.

  • Macrophage-specific deletion of H-PGDS abolishes the protective effects of niacin against pulmonary hypertension in mice.

Niacin is a longstanding lipid-lowering drug with a relatively safe pharmacological profile. In this study, we demonstrate that niacin suppresses pulmonary vascular remodeling in rodent models of pulmonary arterial hypertension. Niacin stimulates prostaglandin D2 release through H-PGDS, but not lipocalin-type PGDS in lung tissues. H-PGDS is expressed dominantly in infiltrating macrophages in the lungs from pulmonary arterial hypertension. Macrophage-specific deletion of H-PGDS aggravates hypoxia-induced pulmonary hypertension in mice and abrogates niacin’s protective effect on pulmonary hypertension. These findings support the potentially beneficial effect for niacin therapy on pulmonary arterial hypertension.

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