Involvement Of RhoA/Rho-kinase Pathway In Hypoxic-induced Pulmonary Hypertension Rats And The Effects Of Atorvastatin

Objective To investigate atorvastatin reverse established hypoxic pulmonary hypertension rats by inhibiting RhoA/Rho-kinase pathway activityMethods 32 rats were individed into 4 groups:normoxic controls (A), hypoxic controls(B), hypoxic plus atorvastatin -treated (C), hypoxic atorvastatin plus normal sodium-treated (D). Hypoxic groups(B,C,D) were maintained at 10% FIO2 6 hours/d×6days×3weeks. Rats in group C were received 10 mg/kg/d atorvastatin which was diluted at a concentration of lmg/ml. And rats in group D were received the dose of 1 Oml/kg normal sodium instead. After 4weeks, rats were anesthetized and mean pulmonary arterial pressure (mPAP) was measured by right-heart catheterization. The arteriole wall thickness/vascular external diameter (WT%), vascular area/ total vascular area (WA%) were measured by a computerized imageanalyzer. RhoA and phos-MYPT-1 expression in pulmonary artery were tested by western blotting. NF-κB activity in pulmonary artery VSMC were observed by using immunohistochemistry. Results The mPAP, RV/(LV+S), WT%, WA% and the rate of active NF-κB in the group B [(29.6±1.1) mmHg, (39.0±0.7)%,(35.6±2.4)%, (56.5±5.1)% and (32.5±4.4)%] compared to the group A [(16.8±0.7) mmHg, (27.4±0.5)%, (22.3±1.2)%, (36.6±2.3)% and (13.1±1.9)%], the differences were significant (all P<0.05). The mPAP, RV/(LV+S), WT%, WA% and the rate of active NF-κB in the group C[(23.3±3.2)mmHg, (33.3±2.1)%, (28.2±3.2)%, (44.1±2.7)% and (25.6±3.3)%] were higher than these in the group A (all P<0.05), and were lower than those in the group B (all P<0.05). These indexes in group D had no significant differences to the group B. Expression of RhoA and phos-MYPT-1 in pulmonary artery got enhanced in the hypoxic group (B), and were decreased in the atorvastatin-treaed group (C). The activation of Rho-kinase was positively correlated with the mPAP,WT%,WA% and the activation of the NF-κB in pulmonary artery VSMC. (r=0.830,r=0.740,r=0.879,r=0.807, all P<0.01)Conclusions RhoA/Rho-kinase pathway may play an important role in the development of hypoxic pulmonary hypertension. RhoA/Rho-kinase pathway may play an important role in the activity of NF-κB in pulmonary artery VSMC. Atorvastatin may reverse hypoxic pulmonary hypertension by inhibiting RhoA/Rho-kinase activity.