Protective role of metformin against chronic experimental pulmonary arterial hypertension

Background: Our previous study has indicated that activation of AMPK inhibits the proliferation of rat pulmonary artery smooth muscle cells (PASMCs) in vitro through inhibiting the expression of S phase kinase-associated protein 2 (Skp2), which in turn up-regulates the p27 expression. In the present study, we intended to determine whether similar mechanisms have been involved in rat PAH model. Methods: Rat pulmonary arterial hypertension (PAH) model was established by intraperitoneal injection of monocrotaline (MCT). Metformin was administered to activate AMPK. Parameters including the right ventricle systolic pressure (RVSP), the right ventricular hypertrophy (RVH) and the percentage of medial wall thickness were used to evaluate the development of PAH. Immunoblotting was used to determine the phosphorylation and expression of AMPK, and expression of Skp2 and p27. Results: Metformin significantly decreased the RVSP and inhibited the RVH in MCT-induced rat PAH model, and partially inhibited the pulmonary vascular remodeling. These effects were coupled with the decrease of Skp2 and increase of p27 expressions as well as the activation of AMPK. Conclusions: Metformin benefits PAH by inhibiting proliferation of PASMCs and reducing pulmonary vascular remodeling. The present study suggests that metformin might have potential value in clinical treatment of PAH.