Abstract
Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.
Highlights
Abdominal aortic aneurysm (AAA) is a highly lethal disorder characterized by permanent dilatation of the abdominal aorta with an approximately 80% mortality rate upon rupture[1]
We used a drug-repositioning strategy to screen all the compounds that have been integrated into Connectivity Map (CMap) (Fig. 1a, Supplementary Table S1)
Our data highlight the therapeutic potential of interfering with 14-3-3 epsilon and TFEB binding for macrophage TFEB activation in related vascular inflammation
Summary
Abdominal aortic aneurysm (AAA) is a highly lethal disorder characterized by permanent dilatation of the abdominal aorta with an approximately 80% mortality rate upon rupture[1]. AAA is epidemiologically associated with aging, smoking, male sex, high cholesterol, etc., and is mechanistically characterized by chronic aortic wall inflammation, proteolysis of extracellular matrix proteins, and dysfunction of vascular smooth muscle cells[2]. Connectivity Map (CMap) has provided a datadriven and systematic approach for discovering associations among genes, chemicals, and diseases based on genomewide expression profiling[8–11]. Jia et al Cell Discovery (2022)8:21 clinically used tetracycline antibiotic, was proposed to significantly prevent aneurysm formation in animal models based on the observation that aberrant matrix turnover mediated by MMPs plays a pivotal role in the pathogenesis of AAA13,14. Naringenin stimulates TFEBdependent macrophage lysosome biogenesis and inhibits inflammasome activation. Naringenin promotes M2 macrophage polarization and reparative responses via TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6
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