Pulmonary arterial hypertension (PAH) is a fatal disease caused by a narrowing pulmonary artery and ultimately results in an increased risk of right ventricular heart failure, is a rare developing serious blood vessel disease in the lungs [1]. PAH is diagnosed with a mean pulmonary artery pressure greater than 20 mm Hg and certain clinical characteristics, including vascular dysfunction and a progressive increase in arterial obstruction and right ventricular hypertrophy [2]. Despite current treatment for PAH, which consists of conventional single-pathway and combination targeted monotherapy demonstrably, improves morbidity and mortality, the majority of patients with bad right ventricle function and myocardial stress with a high risk of death [3,4]. Thus, it is essential to find new effective molecular targets for pulmonary vascular remodeling and develop more effective therapies for PAH treatment.

Eukaryotic initiation factor 3 subunit A (EIF3A) is a main scaffolding subunit of the EIF3 complex that contributes to carcinoma development [5]. EIF3A appears essential in controlling gene expression, while in all steps of translation initiation, and it widely functions in the cellular, physiological, and pathological processes [6]. EIF3A has been reported to promote the proliferation of a variety of cells, including fibroblasts, hepatic stellate cells, and thyroid cancer cells [[7], [8], [9]]. Recent accumulating evidence suggested that EIF3A was a new anticancer drug target in the EIF family [6]. In addition, EIF3A dysfunction has been implicated in cardiovascular disease and loss of lung function. It has been demonstrated that EIF3A knockdown alleviates pulmonary and myocardial fibrosis [9,10]. EIF3A is highly expressed in a hypoxia-induced rat model of right ventricular remodeling, and restraining its expression alleviates right ventricular remodeling [10]. Similarly, the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) database shows that EIF3A is also highly expressed in pulmonary artery smooth muscle cells (GSE2559/GPL8300/32,785) and lung tissue (GSE113439/GPL6244/7,936,614) of PAH patients [11,12], suggesting that EIF3A is a previously unknown therapeutic method of PAH. However, the role of EIF3A in PAH and the underlying mechanisms has not been explored.

At the molecular level, we here identified histone deacetylases 1 (HDAC1) as a potential target of EIF3A. Firstly, a reanalysis of a dataset on bladder cancer that is downloaded from the GEO database finds that ELF3A positively regulates the expression of HDAC1 [13]. Moreover, there is distinct evidence that inhibition of HDAC1 in PAH patients and animal models contributes to alleviate PAH and inhibits the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [[14], [15], [16]]. Beyond its roles in cancer and PAH, HDAC1 is involved in myocardial dysfunction through its effects on cell proliferation and autophagy via PTEN/AKT/mTOR pathway [17,18]. Emerging evidence indicates that the PTEN/AKT pathways trigger PASMC proliferation and apoptosis imbalance in rats with hypoxic PAH [19]. Furthermore, PI3K/AKT pathway plays an important role in pulmonary vascular remodeling. Inhibition of the PI3K expression and AKT phosphorylation could impede the proliferation of PASMCs and attenuate pulmonary vascular remodeling [20]. Therefore, we hypothesized that EIF3A might mediate its effects on the process of PAH through the regulation of the HDAC1-mediated PTEN/PI3K/AKT pathway.

In the present study, a monocrotaline (MCT)-induced PAH rat model was constructed, and we examined adeno-associated virus serotype 1 (AAV1) mediated knockdown of EIF3A modulated vascular remodeling and PASMC function in the PAH progression. Our in vitro and in vivo results demonstrated that EIF3A/HDAC1 could be a potential molecular axis in PAH progression. The current study suggests that targeting of EIF3A/HDAC1 may suppress the biological abnormalities of PASMCs and eventually block the development of PAH.