Loss of Brg1 prevents the progression of pulmonary hypertension by inhibiting Nrf2 expression

Brahma-related gene 1 (Brg1) is a major factor in regulation of chromatin remodeling and is involved in different cellular processes, including cell proliferation, apoptosis, and differentiation. However, the role of Brg1 in pulmonary artery hypertension (PAH) has not been elucidated. This study aims to assess the role of Brg1 in PAH using hypoxia-induced PAH rat model, Monocrotaline(MCT)-induced PAH rat model, and hypoxia-induced arterial smooth muscle cell model. We found that Brg1 expression was highly expressed in hypoxia-induced PAH rat model and MCT-induced PAH rat model. Moreover, knockdown of Brg1 by injection of adenoviral Brg1 shRNA inhibited Nrf2 expression and its downstream molecular HO-1, attenuated apoptosis resistance, and ameliorated PAH progression in PAH rats. Meanwhile, knockdown of Brg1 suppressed cell proliferation through downregulating the expression of mTOR/P70S6K signaling pathway in vitro and in vivo. In addition, the Nrf2 inhibitor Brusatol treatment significantly inhibited cell proliferation, whereas abrogated by loss of Brg1. In summary, these results demonstrated that loss of Brg1 inhibited PAH progression by downregulating Nrf2 to attenuate cell proliferation and enhance apoptosis, which may provide a new therapeutic target to improve cardiopulmonary function in PAH patients.