GYS2 Promotes the Progression of Aortic Dissection and Aortic Aneurysm via C5a/NF-κB-Mediated Pro-Inflammatory Macrophage Polarization
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Background
Aortic aneurysm and aortic dissection (AAD) are lethal cardiovascular emergencies characterized by sudden onset and extremely high early mortality. The pro-inflammatory polarization of macrophages is one of the core factors driving the pathogenesis of AAD, but its underlying mechanism remains unclear. This study focuses on the aberrant expression of glycogen synthase 2 (GYS2) in the AAD microenvironment and its role in driving macrophage polarization toward the pro-inflammatory M1 phenotype.
Methods
Proteomic analysis was conducted to identify protein heterogeneity associated with AAD. Clinical and animal samples were used to evaluate the correlation between GYS2 expression and AAD progression. Whole-body GYS2 knockout mice and adeno-associated virus (AAV)-mediated macrophage-specific gain- and loss-of-function models were utilized to investigate the regulatory role of GYS2 in macrophage polarization and complement activation. Downstream molecular pathways were identified and validated through in vitro stimulation and in vivo exogenous C5a rescue experiments.
Results
GYS2 expression was significantly upregulated in AAD tissues and primarily localized in macrophages. Activation of GYS2 by LiCl or macrophage-specific overexpression of GYS2 exacerbated aortic dilation and extracellular matrix degradation, and increased mortality in AAD mice. Conversely, whole-body GYS2 knockout or macrophage-specific GYS2 knockdown suppressed inflammatory factors, significantly reduced the incidence of AAD, and attenuated vascular injury. Mechanistically, excessive GYS2 in macrophages specifically triggered the complement-coagulation cascade, promoting the generation of the potent anaphylatoxin C5a. C5a further bound to its receptor C5AR1, activating the downstream PLCβ3/NF-κB signaling pathway, thereby inducing M1 macrophage polarization and matrix metalloproteinase-mediated extracellular matrix degradation. In vivo exogenous C5a rescue completely reversed the vascular protective effects conferred by GYS2 deficiency.
Conclusions
This study demonstrates that highly expressed GYS2 regulates the pro-inflammatory polarization of macrophages and extracellular matrix degradation via the complement C5a/PLCβ3/NF-κB signaling axis, which is a key mechanism driving AAD progression. Specific inhibition of macrophage GYS2 can effectively alleviate aortic vascular inflammation and prevent AAD progression, providing a promising novel strategy for the clinical conservative treatment of AAD.
