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

Abstract 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 (α-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.