Osthole alleviates pulmonary vascular remodeling by modulating microRNA-22–3p mediated lipid metabolic reprogramming

Pulmonary vascular remodeling is the key pathological feature of pulmonary arterial hypertension (PAH) characterized by a pattern of lipid-related insulin resistance(IR), hormonal derangements and metabolic reprogramming. Our previous studies have demonstrated osthole as natural coumarin compound derived from traditional Chinese medicine is a promising agent for the treatment of pulmonary vascular remodeling in PAH.The present study sought to delineate lipid metabolic modulatory mechanism of osthole against pulmonary vascular remodeling by employing an interdisciplinary strategy.Rat model with PAH induced with MCT and PASMCs proliferation model induced with PDGF-BB were established in this study. Serum and lung tissues were used to lipid-related IR, hormone related indexes, pulmonary vascular remodeling analysis. Then, lipid metabolic gene, key enzymes, metabolites and cell proliferation indexes were examined to investigate metabolic regulatory mechanism in vivo and vitro model of PAH.Osthole significantly showed improvement of lipid-related IR and hormone dysregulation in rats with PAH evidenced by elevating testosterone, androgen receptor and cyclic guanosine monophosphate (cGMP), inhibiting phosphodiesterase-5(PDE-5), modulating lipid-related IR indexes total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG)/HDL-C ratio. Additionally, osthole limited key metabolic gene and enzymes to inhibit accumulation of decadienyl-l-carnitine in lipid metabolism, thus to promote oxidative phosphorylation and ATP production through inhibition of miRNA-22-3p, fatty acid translocase (CD36), fatty acid synthase (FAS), phospholipase A2 (PLA2), carnitine palmitoyltransferase 1A (CPT1A), hexokinase 2 (HK2), activation of metabolic switch isocitrate dehydrogenase 3α (IDH3α), NADH dehydrogenase 1 (ND1). We found for the first time miRNA-22-3p modulated PASMCs proliferation and vascular remodeling by regulating lipid metabolism reprogramming. Those modifications uncovered therapeutic mechanism of osthole against pulmonary vascular remodeling.Our findings revealed the function of miRNA-22-3p in PASMCs and demonstrated a novel mechanism that miRNA-22-3p as a regulator can be targeted by osthole to greatly restore dysregulated lipid metabolism thus to alleviate pulmonary vascular remodeling in PAH, which provides novel insight into the potential therapeutic target for PAH, further highlights the development potential of osthole derived new drug against PAH.