Pulmonary Arterial Hypertension in Rats Due to Age-Related Arginase Activation in Intermittent Hypoxia

Abstract

Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (N(ω)-hydroxy-nor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH.

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 inhibition reduced inflammation, airway remodeling and right ventricular hypertrophy in a guinea pig model of chronic obstructive pulmonary disease [ 18 ]. 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 ].…”

An arginase-1 SNP that protects against the development of pulmonary hypertension in bronchopulmonary dysplasia enhances NO-mediated apoptosis in lymphocytes

“…Arginase has two isoforms which are encoded by two distinct genes: arginase-1 (ARG1) on chromosome 6 (Sparkes et al 1986) and arginase-2 (ARG2) on chromosome 14 (Gotoh et al 1997). The induction of arginase is involved in many disease states, including asthma (Morris et al 2004;Morris 2012), sickle cell disease (Morris et al 2005;Morris 2012), vascular diseases (White et al 2006;Morris 2012), and PH (Grasemann et al 2015;Nara et al 2015;Steppan et al 2016). We have previously shown that NOS and arginase compete for their common substrate, L-arginine, such that greater expression and/or activity of one results in lower activity of the other due to limitations in L-arginine bioavailability (Nelin et al 2002(Nelin et al , 2007Chicoine et al 2004;Stanley et al 2006).…”

Correction of morphofunctional disorders with asialoerythropoietin and selective inhibitor of arginase II KUD975 in cases of ischemic kidney damage in the experiment

“…They are associated with blockade of arginase II. When this occurs, eNOS is activated, which leads to the correction of endothelial dysfunction (Suwanpradid et al 2014, Rath et al 2014, Pandey et al 2014, Nara et al 2015, Krause et al 2015, Steppan et al 2016.…”