Thioredoxin system activation is associated with the progression of experimental pulmonary arterial hypertension

• Published in: Life sciences (1973) Vol. 284; p. 119917
• Main Authors: Zimmer, Alexsandra, Teixeira, Rayane Brinck, Constantin, Rosalia Lempk, Fernandes-Piedras, Tânia Regina Gatelli, Campos-Carraro, Cristina, Türck, Patrick, Visioli, Fernanda, Baldo, Guilherme, Schenkel, Paulo Cavalheiro, Araujo, Alex Sander, Belló-Klein, Adriane
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-11-2021; Elsevier BV
• Subjects: AKT protein; Animals; Antioxidants; Antioxidants - metabolism; Apoptosis; Caspase-3; Cell proliferation; Cell signaling process; Cell Survival; Collagen - metabolism; Disease Progression; Electrocardiography; Experimental pulmonary arterial hypertension; Glutathione; Glutathione reductase; Heart Ventricles - metabolism; Heart Ventricles - pathology; Hypertension; Hypertrophy; Hypertrophy, Right Ventricular - complications; Hypertrophy, Right Ventricular - pathology; Injection; Lung diseases; Male; Monocrotaline; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary Arterial Hypertension - complications; Pulmonary Arterial Hypertension - diagnostic imaging; Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - pathology; Pulmonary hypertension; Rats; Rats, Wistar; Reductases; Reduction; Thioredoxin; Thioredoxins - metabolism; Time course; VDUP-1; Vitamin D3; Time course; Cell signaling process; VDUP-1; Thioredoxin; Glutathione reductase; Experimental pulmonary arterial hypertension
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119917

In addition to being an antioxidant, thioredoxin (Trx) is known to stimulate signaling pathways involved in cell proliferation and to inhibit apoptosis. The aim of this study was to explore the role of Trx in some of these pathways along the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male rats were first divided into two groups: monocrotaline (MCT - 60 mg/kg i.p.) and control (received saline), that were further divided into three groups: 1, 2, and 3 weeks. Animals were submitted to echocardiographic analysis. Right and left ventricles were used for the measurement of hypertrophy, through morphometric and histological analysis. The lung was prepared for biochemical and molecular analysis. One week after MCT injection, there was an increase in thioredoxin reductase (TrxR) activity, a reduction in glutathione reductase (GR) activity, and an increase in Trx-1 and vitamin D3 up-regulated protein-1 (VDUP-1) expression. Two weeks after MCT injection, there was an increase in VDUP-1, Akt and cleaved caspase-3 activation, and a decrease in Trx-1 and Nrf2 expression. PAH-induced by MCT promoted a reduction in Nrf2 and Trx-1 expression as well as an increase in Akt and VDUP-1 expression after three weeks. The increase in pulmonary vascular resistance was accompanied by increased TrxR activity, suggesting an association between the Trx system and functional changes in the progression of PAH. It seems that Trx-1 activation was an adaptive response to MCT administration to cope with pulmonary remodeling and disease progression, suggesting a potential new target for PAH therapeutics.
•Thioredoxin-1 (Trx-1) expression is inversely correlated to the Akt activity in lungs of pulmonary hypertensive rats.•Nrf2 modulates positively and VDUP-1 negatively the Trx-1 protein expression.•Cell proliferation, inflammation, and apoptosis were negatively associated with pulmonary Trx-1 expression.•Recycling of Trx-1 by thioredoxin reductase contributes to a decrease in apoptosis signaling.