The role and mechanism of RAS-MAPK/ERK in right heart dysfunction associated with pulmonary hyperten

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  Introduction The cost-effective therapeutic strategy of pulmonary hypertension related right ventricle dysfunction still need further investigate.Objectives To observe the potential effects of Olmesartan on pulmonary hypertension related right ventricle failure in monocrotaline (MCT)-induced rats model and to demonstrate the mechanism of RAS-MAPK/ERK pathway.Methods Twenty-four male Sprague-Dawley rats were randomly divided into 4 groups: Group 1 (control group), Group 2(pulmonary arterial hypertension induced by injection of MCT 60mg/kg, SC.PAH group), Group 3 (Control + Olmesartan 2mg/kg/d, ig)and Group 4 (PAH + Olmesartan 2mg/kg/d, ig).Atter 6 weeks, all survival rats were detected by echocardiography to observe the RV free wall thickness (RVFWT) and RV eject fraction (RVEF).All survival rats were measured by right catheterization to observe PASP, mPAP, RVSP.RVHI were weighted.Right ventricles tissue was staining with haematoxylin-eosin (HE) optical microscope and transmission electron microscopy (TEM).The collagen type I and the collagen type collagen volume fraction (CVF) were detected.Expressions of AT1R, TGF-β1 and ERK1/2 protein of right ventricles tissue were determined by western blot.Results Compared with the group 1, RVFWT , mPAP, RVSP and RVHI significantly increased in group2 and there was no significant difference between group 4 and group 3 (P>0.05).In group 2,the microstructure of right ventricles show cardiac myocyte hypertrophy, interstitial fibrosis and myocardial fiber lined up in disorder, and the ultrastructure of right ventricular cardiac myocyte show mitochondria swell and medullary sheath-like degeneration, the sarcoplasmic reticulum enlarged and the myofilaments dissolves and the Z lines broken.These morphological changes improved to some extent in group 4.Collagen type Ⅰ, collagen type and CVF in group 4 was significantlower than that in group 2 (P<0.01).AT1R, TGF-β1 and ERK1/2 protein expression markedly increased (P<0.01) in group 2.Compared with group 2, AT1R, TGF-β1 and ERK1/2 protein expression in group 4 markedly decreased (P<0.01).Conclusion In MCT-induced pulmonary hypertension related fight ventricular failure rats, AT1R, TGF-β1 and ERK1/2 protein expression of right ventricles were up-regulated.Olmesartan inhibited up-regulation of AT1R, TGF-β1 and ERK1/2 protein expression of right ventricles and it might inhibit collagen type Ⅰ, collagen type and CVF of fight ventricular.
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