Circulating APOH promotes aortic dissection by activating the vascular smooth muscle cell NR5A1–PPARγ pathway

Introductions

Aortic dissection (AD) is a life-threatening vascular disease with limited therapeutic targets. Apolipoprotein H (APOH), a circulating glycoprotein implicated in lipid metabolism, has not been studied in AD.

Methods

Plasma APOH levels and aortic deposition were examined in AD patients. A β-aminopropionitrile (BAPN) and angiotensin II (Ang-II)-induced mouse AD model with AAV-mediated Apoh knockdown was used to evaluate survival, aortic dilation, and extracellular matrix remodeling. Transcriptomic profiling, chromatin immunoprecipitation, and gene silencing in human aortic vascular smooth muscle cells (HAVSMC) were performed to dissect the mechanism. PPARγ agonist rescue was conducted in vivo .

Results

APOH was elevated in plasma and deposited in AD aortas. Apoh knockdown improved survival, reduced AD incidence and ascending aortic dilation, and attenuated elastic fiber disruption and collagen deposition. Transcriptomics revealed enrichment of the PPAR pathway. APOH promoted HAVSMC phenotypic switching from a contractile to a synthetic state, decreasing ACTA2/TAGLN and increasing OPN/MMP9. Mechanistically, APOH upregulated NR5A1, which directly bound the PPARγ promoter to enhance PPARγ and FABP4 expression. Silencing NR5A1 or PPARγ reversed APOH-induced phenotypic switching and inflammation. In vivo , PPARγ agonist diminished the protective effects of Apoh silencing.

Conclusion

APOH promotes AD progression through the NR5A1–PPARγ axis, driving vascular smooth muscle cell phenotypic switching and inflammation, and represents a potential therapeutic target.

Graphical Abstract

Circulating APOH promotes aortic dissection through the NR5A1–PPARγ axis in human aortic vascular smooth muscle cells.

Clinical observations showed that plasma APOH levels were elevated in patients with aortic dissection. Circulating APOH acts on human aortic vascular smooth muscle cells (HAVSMC) and upregulates NR5A1, which binds to the PPARG promoter and enhances PPARγ transcription. Activation of the NR5A1–PPARγ signaling axis promotes the phenotypic transition of HAVSMCs from a contractile phenotype to a synthetic phenotype, as indicated by decreased ACTA2 and TAGLN expression and increased OPN and MMP9 expression, accompanied by enhanced production of the inflammatory mediators IL-6, MCP-1, and TNF-α. Silencing NR5A1 or PPARγ reverses APOH-induced phenotypic switching and inflammatory responses, supporting the critical role of the NR5A1–PPARγ axis in APOH-mediated vascular injury.