Neuronal pentraxin 1 accelerates post-stroke atherosclerosis by inducing endothelial cell senescence

Le résumé fourni par la source

Atherosclerosis (AS) and its complications are the leading causes of death worldwide. Endothelial cell (EC) senescence plays a crucial role in the development of AS by aggravating endothelial erosion and plaque instability. Neuronal pentraxin 1 (NPTX1) is a secreted glycoprotein that plays a key role in various neurological functions, such as synaptic function, plasticity at excitatory synapses, and neurite damage. Although NPTX1 is upregulated in senescent ECs, its role in EC senescence and AS remains unknown. Here, we investigated the role of NPTX1 in ischemic stroke and its potential mechanism in regulating EC senescence and AS. Using a middle cerebral artery occlusion (MCAO) mouse model, we observed dynamic NPTX1 expression: levels were minimal at 1 h post-MCAO but surged by 12 h and persisted for 28 days. Moreover, exogenous NPTX1 administration worsened post-stroke brain injury and blood-brain barrier disruption. Notably, MCAO accelerated both AS progression and EC senescence in vivo, while neuron-derived NPTX1-enriched conditioned medium induced EC senescence in vitro. Mechanistically, RNA sequencing and pharmacological inhibition revealed that NPTX1 promotes human umbilical vein EC senescence via an AKT-related pathway, as confirmed by senescence-associated β-galactosidase staining, impaired tube formation, and altered senescence markers. Critically, adeno-associated virus-mediated NPTX1 knockdown attenuated post-stroke AS and EC senescence in mice. Finally, the knockdown of NPTX1 through a short-hairpin RNA adeno-associated virus ameliorates AS and EC senescence in post-stroke mice. These findings establish NPTX1 as a key regulator of stroke-induced EC senescence and AS pathogenesis, highlighting its therapeutic potential for AS treatment in stroke patients.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.