Key result
PVAT Cers6 knockdown reduces aortic dissection incidence and inflammation via macrophage Fpr2 signaling.
Why the study?
Although Cers6 upregulation and C16:0 ceramide accumulation were observed in thoracic aortic perivascular adipose tissue from aortic dissection mice, their role and underlying mechanism in aortic dissection remained unclear.
Does targeting Cers6/C16:0 ceramide or blocking Fpr2/NF-κB signaling reduce aortic dissection incidence and aortic inflammation in a mouse model of aortic dissection?
Does targeting Cers6/C16:0 ceramide or blocking Fpr2/NF-κB signaling reduce aortic dissection incidence and aortic inflammation in a mouse model of aortic dissection?
Cers6-driven C16:0 ceramide accumulation in thoracic aortic perivascular adipose tissue promotes aortic dissection via macrophage Fpr2/NF-κB signaling, identifying a potential tissue-focused therapeutic target.
May reduce aortic dissection in mouse models via Cers6/Fpr2 inhibition; leaves open translation to human therapy.
BACKGROUND: Perivascular adipose tissue (PVAT) is the endocrine microenvironment closest to the aorta. Using multiomics analysis, we found that Cers6 (ceramide synthase 6) was upregulated and C16:0 ceramide accumulated in thoracic aortic PVAT (taPVAT) from aortic dissection (AD) mice; however, its role and underlying mechanism in AD remain unclear. METHODS: A mouse model of AD was established by combined β-aminopropionitrile and AngII (angiotensin II) administration, followed by proteomic and quantitative lipidomic analyses of taPVAT. Cers6 expression in taPVAT adipocytes was locally manipulated by adeno-associated virus delivery, and exogenous C16:0 ceramide was administered in vivo. Mechanistic studies were performed using adipocyte–bone marrow–derived macrophage (BMDM) coculture and C16:0 ceramide-stimulated BMDMs, combined with transcriptomics, pharmacological inhibition, molecular docking, surface plasmon resonance, cellular thermal shift assay, and small interfering RNA knockdown. WRW4 intervention was evaluated in vivo. Human taPVAT samples were used to validate CERS6/C16:0 ceramide changes and clinical correlations. RESULTS: Cers6 was selectively upregulated in taPVAT from AD mice, accompanied by increased C16:0 ceramide levels. Specific knockdown of Cers6 in taPVAT adipocytes reduced AD incidence and attenuated aortic ECM (extracellular matrix) degradation and inflammation, whereas Cers6 overexpression or exogenous C16:0 ceramide aggravated disease. In vitro, Cers6/C16:0 ceramide enhanced macrophage inflammatory activation, migration, and Mmp9 (matrix metalloproteinase-9) expression via Fpr2 (formyl peptide receptor 2)/NF-κB (nuclear factor-κB) signaling. WRW4 mitigated these pro-AD effects in vivo. Similarly, in human taPVAT, CERS6 and C16:0 ceramide were elevated, and C16:0 ceramide correlated positively with aortic inflammatory gene expression and maximal thoracic aortic diameter. CONCLUSIONS: taPVAT Cers6-driven C16:0 ceramide accumulation promotes AD through macrophage Fpr2/NF-κB signaling, enhancing inflammation and ECM degradation. Targeting taPVAT Cers6 or blocking the Fpr2/NF-κB axis may offer a tissue-focused therapeutic strategy.
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Zhuang et al. (2026) studied Aortic dissection. Cers6 manipulation, exogenous C16:0 ceramide, and WRW4 intervention vs. Control / unmanipulated AD mice was evaluated on Aortic dissection incidence, extracellular matrix degradation, and macrophage inflammation. Cers6-driven C16:0 ceramide accumulation in thoracic aortic PVAT promoted aortic dissection via macrophage Fpr2/NF-κB signaling, while Cers6 knockdown or WRW4 reduced AD incidence and inflammation.
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