Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Hartmut Grasemann; Rupinder Dhaliwal; Julijana Ivanovska; Crystal Kantores; Patrick J McNamara; Jeremy A Scott; Jaques Belik; Robert P Jankov

doi:10.1152/ajplung.00328.2014

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Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Journal article

Peer reviewed

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Hartmut Grasemann, Rupinder Dhaliwal, Julijana Ivanovska, Crystal Kantores, Patrick J McNamara, Jeremy A Scott, Jaques Belik and Robert P Jankov

American journal of physiology. Lung cellular and molecular physiology, Vol.308(6), pp.L503-L510

03/15/2015

DOI: 10.1152/ajplung.00328.2014

PMID: 25595650

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Abstract

Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension.

Bronchopulmonary Dysplasia - enzymology

Lung Injury - pathology

Antibiotics, Antineoplastic - pharmacology

Arginase - metabolism

Bronchopulmonary Dysplasia - pathology

Antibiotics, Antineoplastic - adverse effects

Hypertension, Pulmonary - chemically induced

Hypertension, Pulmonary - prevention & control

Lung - enzymology

Lung Injury - enzymology

Lung Injury - prevention & control

Arginase - antagonists & inhibitors

Vascular Remodeling - drug effects

Hypertension, Pulmonary - enzymology

Disease Models, Animal

Boron Compounds - pharmacology

Lung - pathology

Bronchopulmonary Dysplasia - prevention & control

Rats

Aminocaproates - pharmacology

Bleomycin - adverse effects

Rats, Sprague-Dawley

Collagen - metabolism

Animals

Bronchopulmonary Dysplasia - chemically induced

Bleomycin - pharmacology

Lung Injury - chemically induced

Nitric Oxide - metabolism

Hypertension, Pulmonary - pathology

Arginine - metabolism

Details

Title: Subtitle: Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs
Creators: Hartmut Grasemann - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; hartmut.grasemann@sickkids.ca
Rupinder Dhaliwal - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada
Julijana Ivanovska - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada
Crystal Kantores - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada
Patrick J McNamara - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada
Jeremy A Scott - Faculty of Health and Behavioural Sciences, Division of Biomedical Sciences, Department of Health Sciences, Northern Ontario School of Medicine, Lakehead University, Ontario, Canada; and
Jaques Belik - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada
Robert P Jankov - Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada
Resource Type: Journal article
Publication Details: American journal of physiology. Lung cellular and molecular physiology, Vol.308(6), pp.L503-L510
DOI: 10.1152/ajplung.00328.2014
PMID: 25595650
ISSN: 1040-0605
eISSN: 1522-1504
Grant note: MOP-133664 / Canadian Institutes of Health Research 84290 / Canadian Institutes of Health Research MOP-93596 / Canadian Institutes of Health Research
Language: English
Date published: 03/15/2015
Academic Unit: Stead Family Department of Pediatrics; Neonatology; Internal Medicine
Record Identifier: 9984093463602771

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