Inhibition of glutaminase 1 reduces M1 macrophage polarization to protect against monocrotaline-induced pulmonary arterial hypertension

Abstract

• This study is grounded in theoretical support from previous research and delves into the role of glutaminase 1 (GLS1) in pulmonary arterial hypertension (PAH), exploring its mechanisms and potential therapeutic implications. While prior studies have identified alterations in glutamine metabolism during PAH pathogenesis, the precise mechanisms by which GLS1 regulates macrophage polarization and associated immune-inflammatory responses in the PAH context remain unclear. • Innovation 1: This study is the first to systematically investigate the role of GLS1 in the macrophage phenotype transformation associated with PAH. We demonstrated that GLS1 modulates macrophage M1/M2 polarization, thereby influencing immune-inflammatory responses and vascular remodeling. This finding provides robust theoretical support for considering GLS1 as a novel therapeutic target for PAH. • Innovation 2: We employed the GLS1-specific inhibitor BPTES to analyze its effects on PAH in a rat model. While BPTES has shown significant implications in cancer therapy by inhibiting critical metabolic pathways, reducing tumor growth and metastasis, and enhancing the efficacy of other anticancer drugs, its application to PAH models and pharmacological mechanisms represents a novel approach. Our study highlights the promising therapeutic potential of BPTES for PAH, laying a theoretical foundation for future preclinical and clinical investigations. • Innovation 3: Our research is supported by clinical data obtained from public databases and experimental analysis using blood samples from PAH patients. This approach enhances the clinical relevance of our findings, making them more applicable to real patient populations and facilitating validation in clinical settings. • Innovation 4: We employed a multi-faceted experimental design, including in vivo studies using a PAH rat model induced by wild-type alkaloids for drug intervention, and in vitro studies using bone marrow-derived macrophages and alveolar macrophages to explore detailed mechanisms. Additionally, we investigated the effects of GLS1 on pulmonary artery smooth muscle cell behavior. This comprehensive experimental approach strengthens the reliability and scientific rigor of our findings. (1) Metabolic abnormalities and immune inflammation are key elements within pathogenesis of pulmonary arterial hypertension (PAH). And in PAH patients, aberrant glutamine metabolism has been observed; however, the function of glutaminase 1 (GLS1) in macrophage is still unknown. So we aims to investigate GLS1′s impact upon macrophages in PAH. (2) We firstly constructed an monocrotaline (MCT)-induced PAH rat model. Briefly, the PAH rats were treated with the GLS1 inhibitor BPTES, and various index were evaluated, including hemodynamics, right ventricular function, pulmonary vascular remodeling, macrophage markers, and glutamine metabolism. After that, we polarized bone marrow-derived macrophages (BMDMs) into M1 phenotype and then subjected to BPTES intervention. Finally, we assessed macrophage phenotype, inflammatory markers, and glutamine metabolism indicators, along with the impact of BMDM supernatant on the behavior of pulmonary arterial smooth muscle cells (PASMCs). (3) : GLS1 was significantly upregulated in both PAH patients and rats. Treatment with the GLS1 inhibitor BPTES markedly improved pulmonary arterial pressure, right ventricular function, and pulmonary vascular remodeling in PAH rats, while inhibiting M1 macrophage polarization, NLRP3 activation, and the release of pro-inflammatory cytokines. This, in turn, alleviated the proliferation and migration of PASMCs induced by inflammatory stimuli. (4) : We propose that targeting GLS1 to reduce M1 macrophage polarization and inflammatory responses may represent a promising therapeutic approach for PAH.

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