Effects of MuRF1 on hypoxia-induced pulmonary hypertension in mice and underlying mechanism

AIM To explore the effect of MuRF1 on hypoxia-induced pulmonary hypertension (HPH) and its underlying mechanism.

METHODS MuRF1 knockout (KO) mice and their wild type (WT) littermates were randomly allocated to 4 groups: WT group (nWT), WT+HPH group (hWT), KO group (nMuRF1-KO) and KO+HPH group (hMuRF1-KO). hWT group and hMuRF1-KO group were placed in low-pressure and low-oxygen artificial experimental chamber, and nWT group and nMuRF1-KO group were placed in atmospheric oxygen SPF environment for 28 days. The cardiac function and the remodeling level of right ventricle, the remodeling level of distal pulmonary artery, the expression of inflammatory factors in bronchoalveolar lavage fluid (BALF) and the expression levels of MuRF1 and BK-β1 were determined in mice.

RESULTS Compared with those in nWT group, RVID was significantly decreased (P<0.01), with up-regulated RVAW, RVSP, RVHI and CVF (P<0.01), and enhanced WT%, WA%, distal pulmonary artery muscularization, relative lung weight and the levels of IL-1β, IL-6, TNF-α in BALF (P<0.01), as well as increased MuRF1 (P<0.05) and decreased BK-β1 (P<0.05) expression in the lung tissue in hWT group. Compared with those in hWT group, RVID was significantly increased (P<0.05), with down-regulated RVAW, RVSP, RVHI and CVF (P<0.05), and decreased WT%, WA%, distal pulmonary artery muscularization and relative lung weight and the levels of IL-1β, IL-6, TNF-α in BALF (P<0.05, P<0.01), as well as decreased MuRF1 (P<0.01) and increased BK-β1 expression (P<0.05) in the lung tissue in hMuRF1-KO group.

CONCLUSION MuRF1 knockout improves right ventricular dysfunction and right ventricular remodeling, and alleviates pulmonary vascular remodeling and inflammatory environment of pulmonary vessels in HPH mice, which may be related to the inhibition of BK-β1 degradation by MuRF1 knockout.