LncAAT-mediated decline in energy metabolism is essential for vascular endothelial senescence in advancing age

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ID: 337971
2026
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Abstract
AIMS: Vascular endothelial senescence is a critical contributor to the development of cardiovascular disease and energy production deficiency plays a pivotal role in cellular senescence. Long noncoding RNAs (lncRNAs) are increasingly recognized as key regulators in biological aging processes. However, their involvement in energy metabolism and its relationship with endothelial senescence remains poorly understood. METHODS AND RESULTS: LncRNA microarray analysis was performed to profile lncRNAs using young and aged human aortas, and we identified a novel lncRNA, Aging Associated Transcript (lncAAT), which was predominantly localized in the nucleus of vascular endothelial cells and exhibited age-dependent increase. Endothelial-specific knockout of lncAAT in mice delayed vascular aging, enhanced endothelial-mediated vasodilation, and improved angiogenesis in a hindlimb-ischemia model. RNA-sequencing showed that lncAAT knockdown upregulated genes associated with energy metabolism including glycolysis and oxidative phosphorylation. LncAAT overexpression mediated fall in energy production led to endothelial senescence in vivo and in vitro. Mechanistically, lncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry analysis found that AAT interacted with pyruvate kinase isozyme type M2 (PKM2) located at the nucleus. The lncAAT-PKM2 complex competitively blocked the interaction between PKM2 and STAT3, impairing energy metabolism gene transcription and ultimately leading to endothelial senescence. CONCLUSION: Our current findings firstly reveal the essential role of lncAAT in promoting vascular endothelial senescence through defective energy metabolism. Inhibition of lncAAT expression presents a promising therapeutic strategy for alleviating vascular aging and reducing the burden of cardiovascular diseases in humans.
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openalex_W7224996959 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors
Journal cardiovascular research
Year 2026
DOI
10.1093/cvr/cvag262
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