Daile Jia1,2,3, Peiyuan Bai2,3, Naifu Wan3,4, Jiao Liu1,5, Qian Zhu3,4, Yuhu He3, Guilin Chen1, Jing Wang6, Han Chen7, Chen Wang7, Ankang Lyu4, Michael Lazarus8, Yunchao Su9, Yoshihiro Urade10, Ying Yu1,3,5, Jian Zhang1, Yujun Shen1. 1. Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (D.J., J.L., G.C., Y.Y., J.Z., Y. Shen). 2. Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (D.J., P.B.). 3. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China (D.J., P.B., N.W., Q.Z., Y.H., Y.Y.). 4. Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (N.W., Q.Z., A.L.). 5. Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (J.L., Y.Y.). 6. Cardiology, Cardiovascular Institute and Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China (J.W.). 7. Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China (H.C., C.W.). 8. International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba City, Japan (M.L.). 9. Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Georgia, United States of America (Y. Su). 10. Isotope Science Center, The University of Tokyo, Tokyo, Japan (Y.U.).
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.
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: Derek Strassheim; Timothy Sullivan; David C Irwin; Evgenia Gerasimovskaya; Tim Lahm; Dwight J Klemm; Edward C Dempsey; Kurt R Stenmark; Vijaya Karoor Journal: Cells Date: 2021-11-29 Impact factor: 7.666