Arginase Inhibition Reverses Monocrotaline-Induced Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a heterogeneous disorder associated with a poor prognosis. Thus, the development of novel treatment strategies is of great interest. The enzyme arginase (Arg) is emerging as important player in PH development. The aim of the current study was to determine the expression of ArgI and ArgII as well as the effects of Arg inhibition in a rat model of PH. PH was induced in 35 Sprague–Dawley rats by monocrotaline (MCT, 60 mg/kg as single-dose). There were three experimental groups: sham-treated controls (control group, n = 11), MCT-induced PH (MCT group, n = 11) and MCT-induced PH treated with the Arg inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; MCT/NorNoha group, n = 13). ArgI and ArgII expression was determined by immunohistochemistry and Western blot. Right ventricular systolic pressure (RVPsys) was measured and lung tissue remodeling was determined. Induction of PH resulted in an increase in RVPsys (81 ± 16 mmHg) compared to the control group (41 ± 15 mmHg, p = 0.002) accompanied by a significant elevation of histological sum-score (8.2 ± 2.4 in the MCT compared to 1.6 ± 1.6 in the control group, p < 0.001). Both, ArgI and ArgII were relevantly expressed in lung tissue and there was a significant increase in the MCT compared to the control group (p < 0.01). Arg inhibition resulted in a significant reduction of RVPsys to 52 ± 19 mmHg (p = 0.006) and histological sum-score to 5.8 ± 1.4 compared to the MCT group (p = 0.022). PH leads to increased expression of Arg. Arg inhibition leads to reduction of RVPsys and diminished lung tissue remodeling and therefore represents a potential treatment strategy in PH.

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

“…These data are consistent with the recent detection of a protective SNP variant in Arg1 that results in decreased arginase activity against development of pulmonary hypertension in at-risk infants with bronchopulmonary dysplasia [83]. The potential therapeutic application of this finding has been demonstrated in rats exposed to monocrotaline, where pharmacologic arginase was inhibited by administration of the small molecular inhibitor Nω-hydroxy-nor- l -arginine (nor-NOHA), ameliorating pulmonary hypertension and diminishing lung tissue remodeling [84]. …”

Arginine Therapy for Lung Diseases

“…Increased serum arginase activity and more specifically, endothelial arginase II expression, low plasma L -arginine levels and low l--arginine:ADMA ratios have been described in patients with both primary and secondary PH ( Morris et al, 2003 ; Xu et al, 2004 ; Morris et al, 2005 ; Kao et al, 2015 ). Arginase inhibition has been shown to prevent right ventricular hypertrophy in a guinea pig model of COPD ( Pera et al, 2014 ) and reduce the elevated right ventricular systolic pressure in various animal models of PH ( Jiang et al, 2015 ; Grasemann et al, 2015a ; Jung et al, 2017 ). Arginase inhibition has also been shown to inhibit the hypoxia-induced proliferation of human pulmonary arterial smooth muscle cells ( Jiang et al, 2015 ; Chu et al, 2016 ), implicating that increased arginase activity could also contribute to vascular remodeling in PH.…”

Focus on Early Events: Pathogenesis of Pulmonary Arterial Hypertension Development

“…Together with adventitial fibroblasts activation, this could involve profibrotic changes in the vasculature. Also, elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (NOS), and the upregulation of arginases (75, 174) could increase the consumption of arginine via the urea cycle with a 14-fold increase in urea, ornithine, and polyamines content. All these events indicate a disrupted arginine homeostasis and suggest the bypass of normal nitric oxide (NO) signaling.…”