ROS-activated CD147-type I interferon signaling axis drives vascular smooth muscle cell fate transition and abdominal aortic aneurysm progression
The transition of healthy contractile vascular smooth muscle cells to an inflammatory and senescent phenotype is a key driver of abdominal aortic aneurysm (AAA). Although CD147 is highly expressed in VSMCs and upregulated in aneurysmal tissue, the precise role of VSMC-derived CD147 in phenotypic swi...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725002939 |
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| Summary: | The transition of healthy contractile vascular smooth muscle cells to an inflammatory and senescent phenotype is a key driver of abdominal aortic aneurysm (AAA). Although CD147 is highly expressed in VSMCs and upregulated in aneurysmal tissue, the precise role of VSMC-derived CD147 in phenotypic switching and AAA pathogenesis remains elusive. Here, we identified a previously unrecognized nuclear localization of CD147 in VSMCs, and pathological stimuli upregulated the nuclear CD147 expression through reactive oxygen species-dependent mechanisms. Multi-omics analysis integrating RNA sequencing, CUT&Tag, and protein interactome profiling revealed that nuclear CD147 directly interacts with the STAT1/STAT2 complex to activate the IRF7-IFNα/β axis under oxidative stress (H2O2 exposure), thereby driving VSMC senescence and inflammatory reprogramming. Functionally, CD147 deletion in VSMCs significantly mitigated Angiotensin II- and CaPO4-induced AAA formation, accompanied by improved VSMC phenotype, reduced vascular inflammation and extracellular matrix degradation in vivo. Pharmacological inhibition of CD147 using Myricetin, a food-derived natural small-molecule compound, effectively discouraged oxidative stress-induced VSMC fate transition in vitro, and suppressed AAA progression and improved vascular integrity in two murine AAA models, underscoring its therapeutic potential. Collectively, these findings identify CD147 as a key driver of interferon-mediated VSMC fate transition, providing mechanistic insights into AAA progression and a promising therapeutic target for vascular diseases. |
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| ISSN: | 2213-2317 |