Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodelling (PVR). The imbalance between the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important cause of PVR leading to PAH. Mitochondria play a key role in the production of hypoxia‐induced pulmonary hypertension (HPH). However, there are still many issues worth studying in depth. In this study, we demonstrated that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 like 2 (NDUFA4L2) was a proliferation factor and increased in vivo and in vitro through various molecular biology experiments. HIF‐1α was an upstream target of NDUFA4L2. The plasma levels of 4‐hydroxynonene (4‐HNE) were increased both in PAH patients and hypoxic PAH model rats. Knockdown of NDUFA4L2 decreased the levels of malondialdehyde (MDA) and 4‐HNE in human PASMCs in hypoxia. Elevated MDA and 4‐HNE levels might be associated with excessive ROS generation and increased expression of 5‐lipoxygenase (5‐LO) in hypoxia, but this effect was blocked by siNDUFA4L2. Further research found that p38‐5‐LO was a downstream signalling pathway of PASMCs proliferation induced by NDUFA4L2. Up‐regulated NDUFA4L2 plays a critical role in the development of HPH, which mediates ROS production and proliferation of PASMCs, suggesting NDUFA4L2 as a potential new therapeutic target for PAH.

Atherosclerosis (AS) is a systemic disease associated with lipid metabolic disorders and abnormal proliferation of smooth muscle cells. Baicalin is a flavonoid compound isolated from the dry roots of Scutellaria baicalensis Georgi and exerts anti‑proliferative effects in various types of cells. However, the effect of baicalin on AS remains unclear. In the present study, serum samples were collected from patients with AS and an in vitro model of AS was established using oxidized low‑density lipoprotein (ox‑LDL)‑treated human aorta vascular smooth muscle cells (HA‑VSMCs). The siRNA transfection and overexpression efficiency of endogenous maternally expressed gene 3 (MEG3) and the expression level of MEG3 were analyzed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The effects of alterations in expression levels of MEG3 were assessed by MTT assay, bromodeoxyuridine incorporation assay, 5‑ethynyl‑2'‑deoxyuridine staining, wound healing assay, immunofluorescence and western blotting in HA‑VSMCs. qPCR indicated that the expression of MEG3 was reduced in serum samples from patients with AS and ox‑LDL‑treated HA‑VSMCs, compared with serum samples from healthy patients and untreated HA‑VSMCs, respectively. Further experiments indicated that ox‑LDL‑induced decrease of MEG3 expression was reversed by treatment with baicalin in a concentration‑dependent manner. Following treatment with ox‑LDL, decreased expression of MEG3 promoted proliferation and migration, and suppressed apoptosis in HA‑VSMCs. Furthermore, treatment with baicalin reversed these effects on proliferation and apoptosis in ox‑LDL‑treated HA‑VSMCs. The current study indicated that downregulated expression of MEG3 increased cell cycle‑associated protein expression. However, treatment with baicalin inhibited the expression of cell‑cycle associated proteins in HA‑VSMCs with MEG3 knockdown. In addition, baicalin activated the p53 signaling pathway and promoted the expression and transport of p53 from the cytoplasm to nucleus following MEG3 knockdown in ox‑LDL‑treated HA‑VSMCs. Baicalin inhibited proliferation and promoted apoptosis by regulating the expression of MEG3/p53, indicating that baicalin may serve a role in AS by activating the MEG3/p53 signaling pathway. The present study suggested a potential mechanism underlying the protective role of baicalin in the in vitro model of AS, and these results may be used to develop novel therapeutic approaches for the affected patients.