Effects of dose and timing of adipose-derived stem cell transplantation on pulmonary arterial pressure in monocrotaline-induced pulmonary arterial hypertension in rats

Abstract

Objective To investigate the effect of dose and timing of adipose-derived stem cells (ADSC) transplantation on pulmonary arterial pressure in monocrotaline (MCT) -induced pulmonary arterial hypertension (PAH) in rats. Methods (1) MCT-induced PAH in rats: 48 male SD rats were injected intraperitoneally with normal saline, 20 mg/kg, 30 mg/kg and 40 mg/kg MCT respectively. Mean pulmonary arterial pressure (mPAP) was determined by right heart catheterization and right ventricular hypertrophy index (RVHI) was detected by weighting method at 4 and 8 weeks after MCT injection. (2) Dose of ADSC: male SD rats were administrated with 40 mg/kg MCT (n = 30) and normal saline (n = 30). Normal saline or different numbers of ADSC (0.5×106, 1.0×106, 3.0×106, 5.0×106) were injected through jugular vein at 1 week after intraperitoneal injection of MCT. mPAP and RVHI were detected at 3 weeks after ADSC transplantation. (3) Timing of ADSC transplantation: 30 male SD rats were administrated with 40 mg/kg MCT (n = 30) and normal saline (n = 6). One day, 1 or 2 weeks after intraperitoneal injection of 40 mg/kg MCT, 1.0×106 ADSC were transplanted into the rats. mPAP and RVHI were detected at 4 weeks after MCT injection. Differences among groups were compared using one-way or two-way analysis of variance, and pairwise comparison was performed using LSD test. Results (1) 4 weeks after intraperitoneal injection of 30 or 40 mg/kg MCT, both mPAP and RVHI increased [mPAP (mm Hg): 24.89±3.31, 27.19±2.11 vs 15.80±0.42, P < 0.05; RVHI: 0.42±0.06, 0.47±0.04 vs 0.25±0.02, P < 0.05)]. 8 weeks after MCT injection, mPAP and RVHI returned to normal in the 20 and 30 mg/kg MCT groups. All rats died in the 40 mg/kg MCT group. (2) Both mPAP and RVHI in the 40 mg/kg MCT group elevated. 3 weeks after transplantation of 1.0×106 ADSC, mPAP declined (27.19±1.73) mmHg vs (17.24±0.66) mmHg (P < 0.05). However, mPAP did not decrease in rats given 0.5×106, 3.0×106 or 5.0×106 ADSC. (3) 1 or 2 weeks after intraperitoneal injection of 40 mg/ kg MCT, mPAP reduced in PAH rats given 1.0×106 ADSC. Conclusions 4 weeks after a single intraperitoneal injection of 40 mg/kg MCT, a stable PAH rat model could be established. 1 or 2 weeks after intraperitoneal injection of 40 mg/kg MCT, transplantation of 1.0×106 ADSC could effectively reduce mPAP in PAH rats. Key words: Adipose tissue-derived stem cell; Pulmonary arterial hypertension; Monocrotaline; Mean pulmonary arterial hypertension