Maxingxiongting mixture attenuates hypoxia pulmonary arterial hypertension to improve right ventricular hypertrophy by inhibiting the rho-kinase signaling pathway

OBJECTIVE: To explore the mechanism of Maxingxiongting mixture(MXXTM) on pulmonary hypertension in a rat model established by intraperitoneal injection of monocrotaline solution, smoking and forced swimming.METHODS: A total of 30 male Sprague-Dawley rats were randomly divided into five groups: control group, model group, high-dose of MXXTM group(HM), low-dose of MXXTM group(LM), and fasudil group. The mean pulmonary artery pressure(m PAP) was measured by using a miniature catheter. Lung tissue and right ventricular tissue sections were stained with hematoxylin-eosin. The right ventricle(RV) and left ventricle + septum(LV + S) were weighted. RV/(LV + S) was calculated to reflect the degree of right ventricular hypertrophy. Rho/Rho-kinase signaling pathway key proteins(Rho A,ROCK Ⅰ and ROCK Ⅱ) in rat right ventricular tissue were measured by Western blot analysis. The levels of serum hypoxia-inducible factor-1α(HIF-1α), vascular endothelial growth factor(VEGF) and the levels of plasma renin activity(PRA), angiotensin Ⅱ(ANG-Ⅱ), aldosterone(ALD) in rat anticoagulated plasma were all measured by enzyme-linked immunosorbent assay.RESULTS: Compared with the control group, the m PAP and RV/(LV+S) in the model group were significantly increased. Administration of fasudil resulted in a significant decrease of m PAP and RV/(LV+S). In the HM group and LM group, m PAP and RV/(LV + S) were significantly lower than the model group. Compared with the control group, the contents of HIF-1α, VEGF, PRA, ANG-Ⅱ and ALD in the model group were significantly increased. The administration of fasudil and high-dose MXXTM significantly reduced the contents of HIF-1α, VEGF, PRA,ANG-II and ALD. Compared with the control group,the expression of Rho A, ROCK Ⅰ and ROCK Ⅱ in the right ventricle of the model group were significantly increased. The administration of fasudil and high-dose MXXTM significantly reduced the expression of Rho A and Rock Ⅱ proteins. Our results indicated that high-dose of MXXTM had similar effects on reducing pulmonary artery pressure and improving right ventricular remodeling to fasudil.However, MXXTM was unable to restore parameters above to control levels.CONCLUSIONS: MXXTM attenuates hypoxia pulmonary arterial hypertension to improve right ventricular hypertrophy by inhibiting the Rho-kinase signaling pathway.