Response gene to complement32 in inflammatory smooth muscle transformation
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[EMBARGOED UNTIL 12/01/2026] Abdominal aortic aneurysm (AAA) is characterized by chronic inflammation, extracellular matrix (ECM) degradation, and vascular smooth muscle cell (VSMC) phenotypic switching, yet no effective pharmacological therapies exist to prevent disease progression. The regulatory mechanisms governing VSMC phenotypic plasticity during vascular inflammation remain insufficiently defined. Here, we studied if Response Gene to Complement 32 (RGC32) regulates VSMC phenotype under inflammatory conditions. In human smooth muscle cells (HSMCs), treatment with IL-1β and TNF-α led to a rapid and sustained downregulation of RGC32 expression at both mRNA and protein levels, coinciding with the transition from a contractile to an inflammatory/synthetic state. Overexpression of RGC32 counteracted cytokine-induced loss of contractile markers, restoring α-SMA, 22α, and CNN1 expression. Notably, RGC32 overexpression suppressed MMP2 expression under inflammatory stimulation, suggesting a protective role against ECM breakdown and aortic wall weakening. RNA sequencing further revealed that RGC32 reshapes global gene expression programs, enhancing ECM-related gene signatures (e.g., COL1A1, ELN, C1Q) while modulating chromatin remodeling, RNA processing, and protein turnover pathways. These findings indicate that RGC32 functions may serve as a molecular brake that stabilizes VSMC identity and regulates ECM homeostasis during vascular inflammation.
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M.S.