title: Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia.
abstract: Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. L-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-L-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders.
authors.affiliation: Department of Respiration, Jinan Central Hospital Affiliated to Shandong University, 105 JieFang Rd, Ji'nan, 250013, Shandong, China.
authors.forename: YanBiao
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Surgery, Qilu Hospital, Shandong University, Ji'nan, 250012, Shandong, China.
authors.forename: XiaoYing
authors.initials: X
authors.lastname: XiangLi
authors.affiliation: Department of General Surgery, The Fourth People's Hospital of Ji'nan, The Second Affiliated Hospital of Tai Shan Medical College, Ji'nan, 250031, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Niu
authors.affiliation: Department of Respiration, Jinan Central Hospital Affiliated to Shandong University, 105 JieFang Rd, Ji'nan, 250013, Shandong, China.
authors.forename: HongChao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Respiration, Jinan Central Hospital Affiliated to Shandong University, 105 JieFang Rd, Ji'nan, 250013, Shandong, China.
authors.forename: PingDong
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Respiration, Jinan Central Hospital Affiliated to Shandong University, 105 JieFang Rd, Ji'nan, 250013, Shandong, China.
authors.forename: WenBin
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital, Shandong University, Ji'nan, 250012, Shandong, China.
authors.forename: DaWei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Critical Care Medicine, Qilu Hospital, Shandong University, Ji'nan, 250012, Shandong, China.
authors.forename: WeiDong
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Respiration, Jinan Central Hospital Affiliated to Shandong University, 105 JieFang Rd, Ji'nan, 250013, Shandong, China. respirat@163.com.
authors.forename: ChunYan
authors.initials: C
authors.lastname: Xing
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D066253:Vascular Remodeling
chemical_list: D004791:Enzyme Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D001119:Arginase
keywords: Arginase; Hypoxia; Pulmonary arterial hypertension; Pulmonary artery smooth muscle cells