Rapamycin reduced pulmonary vascular remodelling by inhibiting cell proliferation via Akt/mTOR signalling pathway down-regulation in the carotid artery-jugular vein shunt pulmonary hypertension rat model

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease. However, effective treatments for PAH are rare. This study aimed to investigate the inhibitory effects of rapamycin on PAH in the carotid artery-jugular vein (CA-JV) shunt PAH rat model as well as the mechanism underlying these effects. METHODS: Twenty-four Sprague-Dawley rats were randomized into the following 3 groups: a control group, a CA-JV shunt group and a treatment group. Rapamycin (2 mg/kg/day) was administered to the treatment group, and placebo was administered to the CA-JV shunt group. Haemodynamic evaluations, pulmonary tissue samplings for morphometry and immunofluorescence and western blot analyses were performed to evaluate the effects of rapamycin on PAH. RESULTS: Rapamycin attenuated the increase of right ventricular systolic pressure (RVSP) and the right ventricular (RV) hypertrophy (RVSP: CA-JV vs CA-JV + rapamycin, P = 0.017; RV: CA-JV vs CA-JV + rapamycin, P = 0.022), as well as the intrapulmonary vessel thickening (thickness index: CA-JV vs CA-JV + rapamycin, P = 0.028; area index: CA-JV vs CA-JV + rapamycin, P = 0.014), induced by overcirculation of the pulmonary vasculature in the CA-JV shunt-induced PAH rat model. Rapamycin decreased the expression level of the indicated cell proliferation marker (a-smooth muscle actin) in the lung vessel and mechanistic target of rapamycin (mTOR) pathway components (p-mTOR: CA-JV vs CA-JV + rapamycin, P = 0.004; p-Raptor: CA-JV vs CA-JV + rapamycin, P = 0.000; p-S6K1: CA-JV vs CA-JV + rapamycin, P = 0.000; p-Akt: CA-JV vs CA-JV + rapamycin, P = 0.001; p-Rheb: CA-JV vs CA-JV + rapamycin, P = 0.000) in pulmonary tissue. CONCLUSIONS: Rapamycin reduced pulmonary vascular remodelling by inhibiting cell proliferation via Akt/mTOR signalling pathway down-regulation in the CA-JV shunt-induced PAH model in rats. Thus, rapamycin may be a novel candidate drug for the treatment of PAH.