INCREASED EXPRESSION OF THE NERVE GROWTH FACTOR (NGF) IN PULMONARY ARTERY IS ACCOMPANIED BY CHANGES OF PARTICULAR MICRORNAS LEVELS IN MONOCROTALINE-INDUCED PULMONARY HYPERTENSION

Abstract

Objective: NGF is a member of the neurotrophin family, whose role has been described in the development and persistence of pulmonary hypertension (PH). Let-7 family is a group of microRNAs that targets NGF and downregulates its expression. On the other hand, microRNA miR-21, has been shown to support NGF signalling, and its expression is increased after NGF stimulation in neuronal cells. Furthermore, miR-21 was reported to contribute to proliferation and migration of lung vascular smooth muscle cells and to decrease BMPR-II expression. In this study, we examined the role of these microRNAs in regulation of NGF expression in pulmonary artery and lungs and, consequently, in the development of experimental monocrotaline-induced PH. Design and method: Male Wistar rats were injected either with monocrotaline (s.c. 60 mg/kg, MCT group) or with vehicle (CON group). Four weeks after MCT treatment, vital functions and right ventricular pressure of rats were measured. Expression of let-7 family, miR-21 and NGF was determined by qRT-PCR in rat pulmonary artery and whole lungs. Results: After MCT administration, we observed decreased oxygen saturation, increased right ventricular pressure and right ventricular hypertrophy (P < 0.05 vs CON). NGF gene expression was significantly increased in pulmonary artery (+106%, P < 0.05 vs CON). In the let-7 microRNA family, expression of two members, namely let-7 g and let-7i was significantly decreased (−31% and −34% respectively, P < 0.05 vs CON), whereas expression of miR-21 was significantly increased (+37%, P < 0.05 vs CON). In lung tissue, we did not note any change in NGF gene expression, together with no significant changes in expression of let-7 family. However, there was a significant increase in miR-21 expression (+92%, P < 0.05 vs CON). Conclusions: The decreased expression of let-7 g and let-7i microRNAs is in line with the increase in NGF expression in pulmonary artery. Additionally, increased miR-21 expression could further enhance NGF signalling. Therefore, we conclude that the let-7 – NGF – miR-21 axis could be a significant contributor to pulmonary vascular pathophysiology in MCT-induced PH.