����˾���Էζ�����ѹ�����������ع������ü�����

Prevention of the Right Ventricular Remodeling by Epalrestat in Pulmonary Arterial Hypertension Rats and the Underlying Mechanisms

??OBJECTIVE To investigate the protective effect of epalrestat on right ventricular remodeling in a rat model of monocrotaline-induced pulmonary arterial hypertension(PAH). METHODS PAH rats were induced by a single injection of monocrotaline(60 mg??kg^-1, sc) and were administered epalrestat(50 or 100 mg??kg^-1) for 4 weeks. At the end of experiment, the right ventricular systolic pressure(RVSP) and mean pulmonary artery pressure(mPAP) were monitored via the right jugular vein catheterization into the right ventricle. Right ventricle(RV) and left ventricle(LV)+septum(S) were isolated and weighed, and ratios of RV/(LV+S)and RV to tibial length were calculated. Right ventricular morphological change was observed by HE staining. Masson??s trichrome stain was used to demonstrate collagen deposition. The total antioxidative capacity(T-AOC) and malondialdehyde(MDA) levels in right ventricle were determined according to the manufacturer??s instructions. The expression of collagen I, collagen ??, AR and NOX4 were analyzed by immunohistochemisty, real-time PCR or Western blot. RESULTS The results showed that epalrestat treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index(RV/LV+S and RV/Tibial length) of PAH rats induced by monocrotaline. Furthermore, monocrotaline-induced right ventricular collagen accumulation and collagen I and collagen III expression were both significantly suppressed by epalrestat. The expressions of AR, NOX4 and MDA content were obviously decreased, while the T-AOC was significantly increased in right ventricular from PAH rats with epalrestat treatment. CONCLUSION These results suggest that epalrestat ameliorates right ventricular remodeling of PAH induced by monocrotaline in rats through its down-regulating of AR and NOX4 expression and collagen accumulation.