The progression of pulmonary arterial hypertension induced by monocrotaline is characterized by lung nitrosative and oxidative stress, and impaired pulmonary artery reactivity

• Published in: European journal of pharmacology Vol. 891; p. 173699
• Main Authors: Zimmer, Alexsandra, Teixeira, Rayane Brinck, Constantin, Rosalia Lempk, Campos-Carraro, Cristina, Aparicio Cordero, Elvira Alicia, Ortiz, Vanessa Duarte, Donatti, Luiza, Gonzalez, Esteban, Bahr, Alan Christhian, Visioli, Fernanda, Baldo, Guilherme, Luz de Castro, Alexandre, Araujo, Alex Sander, Belló-Klein, Adriane
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-01-2021
• Subjects: Animals; Arterial Pressure; Disease Models, Animal; Disease Progression; Endothelial dysfunction; Hypertrophy, Right Ventricular - etiology; Hypertrophy, Right Ventricular - metabolism; Hypertrophy, Right Ventricular - physiopathology; Lung - metabolism; Lung - physiopathology; Male; MCT-Induced experimental pulmonary arterial hypertension; Monocrotaline; Nitrosative Stress; Oxidative Stress; Pulmonary Arterial Hypertension - chemically induced; Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - physiopathology; Pulmonary Artery - metabolism; Pulmonary Artery - physiopathology; Pulmonary Edema - etiology; Pulmonary Edema - metabolism; Pulmonary Edema - physiopathology; Rats; Rats, Wistar; Reactive nitrogen species; Reactive oxygen species; Receptor, Endothelin A - metabolism; Temporal evaluation; Time Factors; Vascular reactivity; Vascular Remodeling; Vasodilation; Endothelial dysfunction; MCT-Induced experimental pulmonary arterial hypertension; Temporal evaluation; Reactive oxygen species; Vascular reactivity; Reactive nitrogen species
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173699

The time-course of pulmonary arterial hypertension in the monocrotaline (MCT) model was investigated. Male rats were divided into two groups: MCT (received a 60 mg/kg i.p. injection) and control (received saline). The MCT and control groups were further divided into three cohorts, based on the follow-up interval: 1, 2, and 3 weeks. Right ventricle (RV) catheterization was performed and RV hypertrophy (RVH) was estimated. The lungs were used for biochemical, histological, molecular, and immunohistochemical analysis, while pulmonary artery rings were used for vascular reactivity. MCT promoted lung perivascular edema, inflammatory cells exudation, greater neutrophils and lymphocytes profile, and arteriolar wall thickness, compared to CTR group. Increases in pulmonary artery pressure and in RVH were observed in the MCT 2- and 3-week groups. The first week was marked by the presence of nitrosative stress (50% moderate and 33% accentuated staining by nitrotyrosine). These alterations lead to an adaptation of NO production by NO synthase activity after 2 weeks. Oxidative stress was evident in the third week, probably by an imbalance between endothelin-1 receptors, resulting in extracellular matrix remodeling, endothelial dysfunction, and RVH. Also, it was found a reduced pulmonary arterial vasodilatory response to acetylcholine after 2 (55%) and 3 (45%) weeks in MCT groups. The relevance of this study is precisely to show that nitrosative and oxidative stress predominate in distinct time windows of the disease progression.
[Display omitted]
•This study looks at MCT-induced pulmonary damage over time (1, 2, and 3 weeks).•MCT induced nitrosative stress after 1 week.•Imbalance in endothelin-1 receptors was associated with oxidative stress.•MCT promoted ECM remodeling, pulmonary reactivity impairment, and RVH.