Effects Of Atorvastatin On BMP/Smad Signaling In Pulmonary Arterial Smooth Muscle Cells Derived From Pulmonary Artery Hypertensive Rats

Objective: To investigate effects of atorvastatin on BMP/Smad signaling inpulmonary arterial smooth muscle cells derived from pulmonary artery hypertensiverats.Methods: Twenty-four Sprague-Dawley rats were randomly assigned into threegroups： control, PAH, statin groups. A dose of40mg/Kg monocrotaline(MCT)intraperitoneally was given in PAH and statin groups to induce pulmonary arterialhypertension(PAH)，and untreated rats were given1ml normal saline intraperitoneallyas control. From the day MCT injection on,rats in statin group were treated withatorvastatin(5mg/kg) by daily gavage for4weeks. Control and PAH groups justreceived vehicle by gavage. Mean pulmonary arterial pressure （MPAP） wasmeasured by catheterizationand; right ventricular hypertrophy index(RVHI) werecalculated[RVHI＝RV/(LV+S)];HE stained were observed for remolding ofpulmonary artery. PASMCs were isolated from normal rats and PAH rats,respectively,by collagenase and papain digestion. Cultured PASMCs isolated from PAH rats weretreated with atorvastatin in the concentrations ranging from0-10-5mol/l for24h.Untreated PASMCs isolated from normal rats were used as control. The mRNAexpressions of BMP2,BMPRⅡ,Smad1and Smad4were determined respectively byRT-PCR, and the protein expressions of BMP2,BMPRⅡ,p-Smad1and Smad4weredetermined respectively by Western Blotting.Result:(1) MPAP and RVHI were higher in PAH group, as compared with controlgroup,while decreased after treatment of atorvastatin.[MPAP: control (15.10±0.72)VS PAH(32.63±0.98)， statin （25.77±0.79）； RVHI： control (24.94±4.66) VSPAH(52.60±3.40)，statin（45.64±1.03），P<0.05](2) The mRNA expressions of BMP2,BMPRⅡ,Smad1and Smad4in PASMCs derived from PAH rats were obviously lower than that from normalrats(P<0.05).Atorvastatin induced an increase in mRNA expressions in the culturedPASMCs derived from PAH rats in a concentration-dependent manner(P<0.05).(3) The protein expressions of BMP2,BMPRⅡ,Smad4and the phosphorylation levelof Smad1in PASMCs derived from PAH rats were obviously lower than that fromnormal rats(P <0.05). Atorvastatin induced an increase in protein expressions andphosphorylation level in the cultured PASMCs derived from PAH rats(P <0.05).Conclusions:(1)The expression of BMP2,BMPRⅡ,Smad4and the phosphorylation level of Smad1were decreased in PASMCs derived from pulmonary artery hypertensive rats inducedby MCT.(2)Atorvastatin alleviated PAH may be related with the up-regulation of theexpression of BMP/Smad signaling.