Magnesium lithospermate B ameliorates hypobaric hypoxia-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition and its potential targets

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling leading to elevation of pulmonary artery pressure, right ventricular hypertrophy, and death. Currently, there are no cure exists for PAH. Magnesium lithospermate B (MLB) is the major component of Salvia przewalskii water extracts with treating angina and cardiovascular damage, anti-inflammation, anti-oxidation and anti-apoptosis. However, the effects of MLB on PAH still unclear. This study we investigated the efficacy of MLB in the hypobaric hypoxia-induced rat model of PAH. The results showed that MLB relieved mean pulmonary arterial pressure (mPAP) and right ventricular hypertrophy index (RVHI). Meanwhile, MLB significantly reduced pulmonary vascular remodeling. Additionally, MLB inhibited hypobaric hypoxia-induced α-smooth muscle actin (α-SMA) expression, cell apoptosis, and α-SMA and von Willebrand factor (vWF) co-expression in lung, suggesting that MLB could inhibit hypobaric hypoxia-induced endothelial-to-mesenchymal transition (EndMT). Furthermore, after treatment with MLB, the expression of hypoxia inducible factor-1α (HIF-1α), nuclear factor-kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 4 (CDK4), CyclinD1, RhoA, rho-associated protein kinase 1 (ROCK1) and ROCK2 was decreased. Further, CHK1, PIM1, STK6, LKHA4, PDE5A, BRAF1, PLK1, AKT1, PAK6, PAK7 and ELNE may be the potential targets of MLB. Taken together, our findings suggest that MLB ameliorates hypobaric hypoxia-induced PAH by inhibiting EndMT in rats, and has potential value in the preventment and treatment of PAH.

Keywords: Endothelial-to-mesenchymal transition; Hypoxia; Magnesium lithospermate B; Potential targets; Pulmonary arterial hypertension.