Phospholysine phosphohistidine inorganic pyrophosphate phosphatase suppresses glycolysis and proliferation of pulmonary artery smooth muscle cells in hypoxic pulmonary hypertension via inhibition of lactate dehydrogenase A

Background: Hypoxic pulmonary hypertension (HPH) is a progressive disorder marked by pulmonary vasculature remodeling, primarily driven by the overproliferation of pulmonary artery smooth muscle cells (PASMCs). Phospholysine phosphohistidine inorganic pyrophosphate Phosphatase (LHPP) has been identified as a tumor suppressor in Cancer. However, its role in the proliferation of PASMCs and its implications in HPH remain unexplored.

Methods: Hypoxia and SU5416 (SuHx) were used to establish HPH rat models. Rat and human PASMCs models with LHPP overexpression and silencing were constructed to evaluate the role of LHPP in HPH. Cell proliferation was assessed using both CCK-8 and EdU assays. LHPP targeting approach (siRNA, adenovirus, and adeno-associated virus AAV) was used for in vitro and in vivo experiments to investigate the impact of LHPP on PASMCs glycolysis. We measured lactate levels, and key glycolytic Enzymes, focusing on LHPP's influence on Lactate Dehydrogenase A (LDHA). Additionally, the effect of methyltransferase-like 3 (METTL3) on the reduction of LHPP expression was examined.

Results: LHPP levels were significantly decreased in both the pulmonary arteries of rats with SuHx-induced HPH and in hypoxia-treated PASMCs. Overexpression of LHPP inhibited the hypoxia-induced increase in proliferation potential and alleviated pulmonary vascular remodeling (PVR) in vivo. Conversely, silencing LHPP promoted PASMCs proliferation. LHPP overexpression suppressed PASMCs glycolysis and proliferation by Lactate Dehydrogenase A (LDHA)-mediated glycolysis. Mechanistic studies revealed that METTL3 downregulated LHPP expression.

Conclusion: This study emphasizes the METTL3/LHPP/LDHA axis's role in enhancing PASMC proliferation and HPH. LHPP may represent a potential therapeutic target for the treatment of hypoxic pulmonary hypertension.

Glycolysis; LDHA; LHPP; METTL3; PASMC; Pulmonary hypertension.