Circulation research · 2026
Sirtuin 1 Activation Mitigates Murine Vasculitis Severity by Promoting Mitophagy.
СтатьяНазвание и аннотация: Перевод в очереди
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Atici Asli E, Jena Prasant K, Carvalho Thacyana T, Ross Benjamin L, Aubuchon Emily A, Lane Malcolm E, Gomez Angela C, Lee Youngho, Fishbein Michael C, Azer Joshua, Mesquita Thassio, Chen Shuang, Crother Timothy R, Arditi Moshe, Noval Rivas Magali
Аннотация
BACKGROUND: SIRT1 (sirtuin 1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, regulates cardiovascular inflammation by modulating cellular stress, inhibiting NLRP3 (NLR family, pyrin domain-containing 3) activation, and promoting the clearance of damaged mitochondria. However, its precise role in the pathogenesis of Kawasaki disease, a pediatric systemic vasculitis that causes coronary artery aneurysms in children, remains unclear.
METHODS: Using the Lactobacillus casei cell wall extract (LCWE) murine model of Kawasaki disease, we evaluated the severity of vasculitis in mice supplemented with nicotinamide adenine dinucleotide precursors, as well as transgenic mice overexpressing SIRT1, and mice with specific deletion of Sirt1 in vascular smooth muscle cells and myeloid cells. Proteomics and echocardiographic analyses were conducted on wild-type and SIRT1-overexpressing mice. We performed immunofluorescent staining, flow cytometry, and Western blot analyses of cardiovascular tissues, heart and abdominal aorta, to assess immune cell infiltration and the expression of proteins related to the autophagy/mitophagy pathway. Western blot analysis was also performed on primary vascular smooth muscle cells to determine the impact of SIRT1 on autophagic flux. The production of proinflammatory 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 nicotinamide adenine dinucleotide precursors or genetic overexpression of SIRT1 significantly reduced the development of LCWE-induced vasculitis, while the specific deletion of Sirt1 in vascular smooth muscle cells or myeloid cells exacerbated vasculitis. Furthermore, overexpression of SIRT1 restored impaired ejection fraction and reduced immune cell infiltrations in LCWE-induced cardiovascular lesions. Proteomics analysis indicated impaired mitophagy/autophagy and the pathogenic synthetic switch of vascular smooth muscle cells in LCWE-injected mice, which was rescued with SIRT1 overexpression and associated with reduced production of proinflammatory cytokines.
CONCLUSIONS: This study reveals an impaired nicotinamide adenine dinucleotide-SIRT1 axis in the pathogenesis of LCWE-induced vasculitis and the therapeutic potential of targeting this axis to reduce cardiovascular lesions and inflammation.
METHODS: Using the Lactobacillus casei cell wall extract (LCWE) murine model of Kawasaki disease, we evaluated the severity of vasculitis in mice supplemented with nicotinamide adenine dinucleotide precursors, as well as transgenic mice overexpressing SIRT1, and mice with specific deletion of Sirt1 in vascular smooth muscle cells and myeloid cells. Proteomics and echocardiographic analyses were conducted on wild-type and SIRT1-overexpressing mice. We performed immunofluorescent staining, flow cytometry, and Western blot analyses of cardiovascular tissues, heart and abdominal aorta, to assess immune cell infiltration and the expression of proteins related to the autophagy/mitophagy pathway. Western blot analysis was also performed on primary vascular smooth muscle cells to determine the impact of SIRT1 on autophagic flux. The production of proinflammatory 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 nicotinamide adenine dinucleotide precursors or genetic overexpression of SIRT1 significantly reduced the development of LCWE-induced vasculitis, while the specific deletion of Sirt1 in vascular smooth muscle cells or myeloid cells exacerbated vasculitis. Furthermore, overexpression of SIRT1 restored impaired ejection fraction and reduced immune cell infiltrations in LCWE-induced cardiovascular lesions. Proteomics analysis indicated impaired mitophagy/autophagy and the pathogenic synthetic switch of vascular smooth muscle cells in LCWE-injected mice, which was rescued with SIRT1 overexpression and associated with reduced production of proinflammatory cytokines.
CONCLUSIONS: This study reveals an impaired nicotinamide adenine dinucleotide-SIRT1 axis in the pathogenesis of LCWE-induced vasculitis and the therapeutic potential of targeting this axis to reduce cardiovascular lesions and inflammation.