Sirtuin 1 Activation Mitigates Murine Vasculitis Severity by Promoting Mitophagy
Year: 2026
Type: article
Abstract: ABSTRACT BACKGROUND Sirtuin 1 (SIRT1), a NAD + -dependent protein deacetylase, regulates cardiovascular inflammation by modulating cellular stress, inhibiting NLRP3 activation, and promoting the clearance of damaged mitochondria. However, its precise role in the pathogenesis of Kawasaki disease (KD), a pediatric systemic vasculitis and the leading cause of acquired heart disease in children, remains unclear. METHODS Using the Lactobacillus casei cell wall extract (LCWE) murine model of KD, we evaluated the severity of vasculitis in mice supplemented with NAD + precursors, as well as transgenic mice overexpressing SIRT1, and mice with specific deletion of Sirt1 in vascular smooth muscle cells (VSMCs) and myeloid cells. Proteomics analysis was performed on the abdominal aortas of WT and SIRT1-overexpressing mice. We performed immunofluorescent staining of cardiovascular tissues to assess the expression of proteins related to the autophagy/mitophagy pathway and the pathogenic switch of VSMCs. Western blot analysis was performed on primary VSMCs and cardiovascular tissues to determine the impact of SIRT1 on autophagic flux. The production of pro-inflammatory cytokines was measured in bone marrow-derived macrophages and peritoneal lavage of transgenic mice using ELISAs. RESULTS SIRT1 expression was downregulated in cardiovascular lesions of LCWE-injected mice, which was associated with a significant reduction of circulating levels of nicotinamide. Supplementation of mice with NAD + precursors or genetic overexpression of SIRT1 significantly reduced the development of LCWE-induced KD, while the specific deletion of Sirt1 in VSMCs or myeloid cells exacerbated vasculitis. Proteomics analysis indicated impaired mitophagy/autophagy and the pathogenic synthetic switch of VSMCs in LCWE-injected mice, which was rescued with SIRT1 overexpression and associated with reduced production of proinflammatory cytokines. CONCLUSIONS This study reveals the presence of an impaired NAD + -SIRT1 axis in the pathogenesis of LCWE-induced KD vasculitis and the therapeutic potential of targeting this axis to reduce cardiovascular lesions and inflammation.
Source: Circulation Research
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Role of neutrophils and eosinophils in bacterial ligand-induced vasculitis, RNA-Mediated Inter-Organelle Communication in Atherosclerosis, Targeting the Sirt-1 pathway to modulate inflammation during murine Kawasaki Disease vasculitis, Role of intestinal microbiome and gut permeability in the development of Kawasaki Disease vasculitis, Role of Sex in Immune Stromal cell Interactions driving cardiovascular lesions in Kawasaki Disease vasculitis, Role of HMGB1 in an experimental model of Bacterial ligand induced Vasculitis
OpenAlex ID: W7161254285