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

2020; Elsevier BV; Volume: 891; Linguagem: Inglês

10.1016/j.ejphar.2020.173699

1879-0712

Alexsandra Zimmer, Rayane Brinck Teixeira, Rosalia Lempk Constantin, Cristina Campos Carraro, Elvira Alicia Aparicio Cordero, Vanessa Duarte Ortiz, Luiza Mezzomo Donatti, Esteban Alberto Gonzalez, Alan Christhian Bahr, Fernanda Visioli, Guilherme Baldo, Alexandre Luz de Castro, Alex Sander da Rosa Araújo, Adriane Belló‐Klein,

Cardiovascular Issues in Pregnancy

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.