Abstract 5662: Reductions in Atrophic E3 Ubiquitin Ligase Expression in Pulmonary Arteries Correlate With the Development of Pulmonary Hypertension
Vascular remodeling in pulmonary hypertensive syndromes is driven by increased activity of nuclear factor of activated T-cells (NFAT) in smooth muscle cells. Although much is known about the regulation of NFAT activity by calcineurin, very little is known about vascular smooth muscle atrophy F-box ubiquitin E3 ligase expression, which targets calcineurin for proteosomal degradation and inhibits pathological hypertrophy. Therefore, we hypothesized the ubiquitin E3 ligases muscle atrophy F-box (MAFbx) and muscle ring finger (MuRF-1) expression would decline during the development of pulmonary hypertension. To investigate this hypothesis, rats were given a single injection of MCT (50 mg/kg i.p.) and indices of pulmonary hypertension (RVSP and RV/LVS) were measured at 0, 7, 14, 28 and 42 days post MCT injection (n=7–10/group). Left and right pulmonary arteries were harvested from each rat at the conclusion of these measures and mRNA expression was assessed by real-time multiplex PCR analysis for MAFbx and MuRF-1. Consistent with our hypothesis, pulmonary vascular smooth muscle MAFbx and MuRF-1 expression were attenuated from 14d to 42d time points compared to 0d when normalized to b-actin mRNA expression, which correlated negatively with RVSP and right ventricular hypertrophy. Interestingly, while treatment with sildenafil from days 28 – 42 reduced RVSP and RV/LVS, MAFbx expression was further compromised. These results suggest that the E3 ubiquitin ligases MAFbx and MuRF-1 may play a role in the development of MCT-induced pulmonary hypertension.