Aloperine Protects Pulmonary Hypertension via Triggering PPARγ Signaling and Inhibiting Calcium Regulatory Pathway in Pulmonary Arterial Smooth Muscle Cells

Previous studies have reported the beneficial role of Aloperine (ALO), an active vasodilator purified from the seeds and leaves of herbal plant Sophora alopecuroides L., on experimental pulmonary hypertension (PH), however, detailed mechanisms remain unclear. In this study, monocrotaline-induced PH (MCT-PH) rat model and primarily cultured rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to investigate the mechanisms of ALO on experimental PH, pulmonary vascular remodeling and excessive proliferation of PASMCs. Results showed that: Firstly, ALO significantly prevented the disease development of MCT-PH by inhibiting right ventricular systolic pressure (RVSP) and right ventricular hypertrophy indexed by Fulton Index, normalizing the pulmonary arterials (PAs) remodeling and improving the right ventricular function indexed by transthoracic echocardiography. ALO inhibited the excessive proliferation of both PAs and PASMCs. Then, isometric tension measurements showed vasodilation of ALO on pre-contracted PAs isolated from both control and MCT-PH rats via activating the KCNQ channel, which was blocked by specific KCNQ Potassium Channel Inhibitor Linopirdine. Moreover, by using immunofluorescence staining and nuclear/cytosol fractionation, we further observed that ALO significantly enhanced the PPARγ nuclear translocation and activation in PASMCs. Transcriptome analyses also revealed activated PPARγ signaling and suppressed calcium regulatory pathway in lungs from MCT-PH rats treated with ALO. In summary, ALO could attenuate MCT-PH through both transient vasodilation of PAs, and chronic activation of PPARγ signaling pathway, which exerted anti-proliferative roles on PASMCs and remodeled PAs.

Aloperine; Peroxisome proliferator-activated receptor γ (PPARγ); Proliferation; Pulmonary arterial smooth muscle cell; Pulmonary hypertension.