ALOX15 and ALOX15B regulate autophagy to promote pulmonary arterial hypertension via the PI3K/AKT/mTOR pathway

Pulmonary arterial hypertension (PAH) is a progressive vascular disorder characterized by endothelial dysfunction, vascular remodeling, and poor prognosis. Arachidonic acid 15-lipoxygenase (ALOX15) and its isoform, arachidonic acid 15-lipoxygenase type B (ALOX15B), are lipid-metabolizing enzymes involved in inflammation, fibrosis, and vascular smooth muscle proliferation. However, their specific roles in pulmonary artery endothelial cells (PAECs), particularly in the regulation of autophagy-a key process in the pathogenesis of PAH remain unclear. This study aimed to investigate the contribution of ALOX15/15B to PAH development through modulation of autophagy in PAECs.

The pathological characteristics of ALOX15/15B in PAH were evaluated using right heart catheterization, echocardiography, immunohistochemistry, and Western blot analysis. Their pathogenic roles were further validated in animal models of PAH induced by chronic hypoxia or by combined exposure to hypoxia and the vascular endothelial growth factor inhibitor Sugen5416. The underlying mechanisms were explored in cultured mouse PAECs.

In a mouse model of PAH, elevated expression of ALOX15B promoted pulmonary arterial wall thickening and remodeling, endothelial cell proliferation and stacking, increased right ventricular systolic pressure, hypertrophy of the right ventricular anterior wall, and impaired tricuspid annular motion, ejection capacity, and overall cardiopulmonary function. Conversely, systemic knockout of ALOX15/15B significantly alleviated these pathological changes. In vitro, the elevated autophagy observed in hypoxic mouse PAECs was markedly reduced by ALOX15/15B small interfering RNA, while subsequent treatment with a PI3K inhibitor restored autophagy, indicating that ALOX15/15B regulate autophagy through the PI3K-AKT-mTOR signaling pathway.

This study identifies a novel mechanism by which ALOX15/15B contribute to PAH progression by modulating autophagy via the PI3K-AKT-mTOR pathway. These findings suggest that ALOX15/15B may represent potential therapeutic targets for PAH.