RETRACTED ARTICLE: Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia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.

Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension

“…As for any other PH animal model available, it has several limitations and some concerns should be kept in mind when interpreting the results obtained with this model [ 32 , 33 ]. Against the background of the fact that most studies investigating the role of Arg in PH development as well as effects of enzyme inhibition were performed using models of hypoxia induced PH [ 19 , 20 , 28 , 35 ], it is of certain scientific interest to elucidate these processes in the MCT model as performed in the current study. Protein expression and tissue distribution analysis clearly showed an increased expression of both, Arg I and Arg II in induced PH compared to controls.…”

“…While for Arg II, a 5.1-fold increase was observable, Arg I revealed a 22.7-fold increase. The finding is novel and its discussion against the background of the available literature is challenging due to most in vivo studies in animal models, predominantly models of hypoxia induced PH, focusing on Arg II, while not comparatively looking for Arg I or even differentiating between the isoforms [ 12 , 18 , 19 , 20 , 21 , 22 , 29 , 36 ]. This might be for the following reasons: first, Arg isoform expression depends on both, the species used for an animal model as well as the pathologic stimulus leading to Arg up-regulation (reviewed in [ 7 ]).…”

“…Arg expression is increased and Arg inhibition prevents PAH development in a rat model of PH induced by intermittent hypoxia suggesting a crucial pathological role of the enzyme [ 19 ]. Human pulmonary artery smooth muscle cells could be evidenced to be an important cell phenotype within the process of hypoxia-induced PH since Arg inhibition significantly attenuated proliferative capacity in these cells [ 20 ]. Arg inhibition could also prevent bleomycin-induced PH, vascular remodeling and collagen deposition in neonatal rats [ 21 ].…”

HIF2α–arginase axis is essential for the development of pulmonary hypertension

“…Blood outgrowth endothelial cells (BOECs) have been extensively used as a model for studying in vitro endothelial function in vascular disorders (29,30) with close functional and gene expression similarity to pulmonary artery endothelial cells (31). Previous work has shown enhanced expression and activity of Arg-2 in PAH patients (27,32). Fig.…”

Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia

“…It has been suggested that arginase activity plays an important role in the pathogenesis of various pulmonary disorders (Maarsingh et al, 2008 ; Durante, 2013 ). For instance, an increase in arginase activity has been associated with several pulmonary and systemic hypertension models (Johnson et al, 2005 ; López et al, 2009 ; Chu et al, 2016 ). Nevertheless, there is no information available about the basal levels of ADMA and homocysteine in animals genetically adapted to life in high altitudes and, therefore, resistant to the development of pulmonary hypertension, such as the llama ( Lama glama ).…”