Colchicine as a therapeutic option for the treatment of pulmonary arterial hypertension (PAH) in a rat model

Abstract

Abstract Introduction Pulmonary arterial hypertension (PAH) is a cardiovascular disease that is characterized by severe structural and functional damages, resulting from the obstructive remodeling of the pulmonary vasculature and consequent right ventricular pressure overload. The current therapy mainly focuses on the pulmonary vascular system, with uncertain efficacy. Therefore, it is crucial to explore new therapeutic approaches. The mechanism of colchicine is complex and not-fully understood, but it has been proven to exert cardiopulmonary protective effects. Methods PAH induction was carried out in 8-week-old male WKY rats with a single subcutaneous injection of 60 mg/kg monocrotaline. Monocrotaline, a pyrrolizidine alkaloid, is metabolized in liver and induces inflammatory processes, which can cause PAH in rats. Starting from day 14 after MCT injection, the animals received three times a week intraperitoneal colchicine treatment at a dose of 0.5 mg/kg for two weeks. Echocardiographic examinations were performed during the study. At the end of the study, besides histological examination of the right ventricles and lungs [arterial wall thickness (WT%) and area (WA%)], the expression and phosphorylation levels of the proteins involved in cardiac remodeling were evaluated using Western blot. We assessed the pyruvate dehydrogenase (PDH) enzyme activity in the heart, which plays an important role in energy metabolism. We also examined the production of cytokines and chemokines in the right ventricle. Results The VW/BW ratio in the colchicine-treated group was significantly reduced compared to the MCT group (p<0.01). Echocardiographic parameters, EF% and E/e' ratio – characterizing the left ventricular function – did not differ considerably between the groups during the treatment. The TAPSE and PAT values characterizing right ventricular function improved in the MCT+C group (p<0.05). Collagen deposition and TGFβ level were significantly reduced by colchicine (p<0.05) in PAH animals. In the MCT+C group, the vascular remodeling (WT% and WA%) significantly decreased compared to the MCT group (p<0.01). The expression of α-SMA in vessel walls was most pronounced in the MCT group (p<0.01), which was significantly reduced by colchicine treatment. The phosphorylation of prosurvival signaling factors (ERK1/2, Akt1, GSK3β) was significantly increased in the MCT+C group (p<0.01) compared to the MCT group. In the right ventricle, PDH enzyme activity increased in the MCT+C group compared to the MCT group (p<0.01). According to cytokine array, cytokines involved in mediating fibrosis and inflammatory processes (TIMP-1, VEGF, L-selectin, CXCL7) showed increased secretion in the MCT group, which was moderately attenuated by colchicine treatment. Conclusion Colchicine treatment reduced the extent of fibrosis and inflammation, improved the structure of the pulmonary vasculature, and enhanced right ventricular function and energy supply.