p16INK4a promoted progress of MCT induced pulmonary hypertension via maintaining redox balance and autophagy pathway.

Abstract

Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and elevated pulmonary arterial pressure. Currently, pathogenesis of PAH remains poorly understood, and therapeutic options are limited. In this study, we aimed to explore role of p16INK4A (p16) in the development of PAH using mouse model induced by monocrotaline (MCT). We utilized p16 knockout mice to investigate protective effects on PAH pathophysiology. Histopathological analysis, Western blotting, and transcriptomic profiling revealed that p16 knockout significantly reduced pathological changes associated with MCT-induced PAH, including vascular remodeling and pulmonary fibrosis. These effects were correlated with enhanced autophagy and balanced oxidative stress response following p16 deletion. Transcriptome analysis indicated that the regulatory impact of p16 on autophagy and oxidative stress was primarily mediated through its modulation of oxidative phosphorylation and glutathione metabolic pathways. Our findings provide new insights in PAH pathogenesis and suggest that targeting p16 may offer novel therapeutic approach for treating PAH. These results highlighted that p16 could be a therapeutic target for modulating autophagy and oxidative stress in PAH, paving the way for future research in this area.