Ero1a, the most strongly hypoxia-induced protein in PASMCs, promotes the development of hypoxia- and monocrotaline-induced pulmonary hypertension in rats

Abstract

Aims

Pulmonary hypertension (PH) is a progressive and life-threatening condition characterized by elevated pressure in the pulmonary circulation, leading to right heart dysfunction and ultimately heart failure. Pulmonary artery smooth muscle cells (PASMCs) are key players in group 3 PH (due to lung diseases and/or hypoxia) progression, where their aberrant proliferation and migration drive vascular remodeling. Dysregulated proteins in PASMCs are critical in PH development. Our research was designed to investigate the most promising potential therapeutic targets for PH.

Materials and methods

Proteomics was used to identify the most significantly upregulated protein in PASMCs under hypoxia. siRNA or plasmid transfection was used to silence or overexpress Ero1a. The proliferation, migration, and apoptosis of PASMCs were assessed respectively. Both hypoxia and monocrotaline-induced pulmonary hypertension model were established in animals. The expression of Ero1a was reduced to explore its role in PH. Bioinformatic analysis were conducted to investigate the signaling pathways involved in the disease progression.

Key findings

Ero1a was confirmed as the most significantly upregulated protein in PASMCs under hypoxia. Silencing Ero1a reduced PASMC proliferation, migration, and apoptosis resistance under both normoxic and hypoxic conditions, while overexpression of Ero1a had the opposite effect. Exposure of rats to hypoxia, along with intraperitoneal injection of MCT solution, induced PH. However, knockdown of Ero1a alleviated all these pathological features. The HIF1-Ero1a-Apelin/APJ signaling axis was speculated to mediate the functional role of Ero1a in PH.

Significance

Our study identifies that targeting Ero1a may represent a promising therapeutic strategy for pulmonary hypertension.