The effect of puerarin on the NLRP3 Inflammasome pathway and MMP-9 in aortic dissection of ApoE-/- mice.

Aortic dissection (AD) is a lethal disease with a rising incidence and few effective preventive measures. This study investigated the therapeutic efficacy of puerarin (Pue) in attenuating AD, with a focused on elucidating its molecular mechanisms through NLRP3 inflammasome and matrix metalloproteinase-9 (MMP-9) modulation. In ApoE-deficient mice, AD mouse model was induced through a 5-week high-fat diet (HFD) feeding regimen followed by a 4-week subcutaneous infusion of angiotensin II (Ang II) via osmotic minipumps (1000 ng/kg/min). Our findings demonstrated that Pue intervention significantly reduced AD incidence and mortality. Furthermore, Pue alleviated hemodynamic stress through systolic blood pressure reduction and restored lipid homeostasis, as evidenced by decreased atherogenic lipids (TG, TC, LDL-C), elevated HDL-C levels, and attenuated aortic lipid deposition. Histopathological analyses revealed Pue preserved aortic integrity via suppression of medial extracellular matrix degradation, collagen disorganization, and elastic fiber fragmentation. Mechanistically, Pue inhibited NLRP3 inflammasome activation, downregulating NLRP3, caspase-1, ASC, and IL-1β expression at both mRNA and protein levels. Concurrently, Pue attenuated the expressions of MMP-9, MMP-2, COL1A1 and COL3A1, which was correlated with reduced co-localization of NLRP3/MMP-9 and CD68/IL-1β in immunofluorescence assays. RNA-seq and WGCNA analyses identified enriched inflammation-related pathways in AD tissues, with Pue reversing NLRP3-associated gene clusters. These findings established Pue as a multi-target phytotherapeutic agent that suppressed AD progression through dual inhibition of the NLRP3 inflammasome activation and MMP-9-mediated extracellular matrix remodeling, offering a promising adjunctive strategy for AD prevention.