Calcineurin/NFAT is a common pathway in rat monocrotaline‐ and hypoxia‐induced pulmonary hypertension

Abstract

The nuclear factors of activated T-cells (NFATs) are calcium sensitive transcription factors regulated by calcineurin. NFATs play critical roles in inflammation and cell proliferation, which are important processes in pulmonary hypertension (PAH) pathogenesis. We hypothesize that NFATs might be the common pathway through which PAH develops. To investigate this hypothesis, we treated monocrotaline (MCT) and hypoxia-induced PAH models with cyclosporine (CsA), a specific calcinurin/NFAT pathway inhibitor, at a dosage of 20 mg/kg/day for 24 days. As a result, right ventricular systolic pressure (RVSP) was suppressed by CsA treatment to 40.5 ± 2.8 mmHg which is otherwise increased to 72.6 ± 4.9 mmHg (p<0.01) in MCT PAH model, compared with CsA treated normal control rat of 24.6 ± 1.7 mmHg. Moreover, right ventricular hypertrophy as reflected by the right ventricle to left ventricle plus septal weight ratio (RV/LV+S) decreased from 0.65 ± 0.04 to 0.38 ± 0.03 (p<0.01) whereas it was 0.28 ± 0.004 in control CsA treated rat. RVSP in hypoxia induced PAH rat was similarly decreased from 51.6% ± 4.3 to 35.1% ± 1.7 (p<0.01) and the RV/LV+S ratio from 0.48 ± 0.01 to 0.35 ± 0.007 (p<0.01) after CsA treatment. Considering the different mechanisms between the MCT- and hypoxia-induced PAH models, we suggest that calcinurin/NFAT pathway is a pivotal common pathway in PAH development.