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Sirtuin 1 Activation Mitigates Murine Vasculitis Severity by Promoting Autophagy and Mitophagy
Asli E Atici1,2, Prasant K Jena1,2, Thacyana T Carvalho1,2
1Department of Pediatrics, Cedars-Sinai Guerin Children's, Cedars-Sinai Health Sciences University, Los Angeles, CA, USA.
Biorxiv : the Preprint Server for Biology
|September 15, 2025
Summary
The NAD+-SIRT1 axis is impaired in Kawasaki disease (KD) vasculitis. Targeting this axis with NAD+ precursors or SIRT1 overexpression may treat KD cardiovascular inflammation.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- Sirtuin 1 (SIRT1) regulates cardiovascular inflammation but its role in Kawasaki disease (KD) is unknown.
- KD is a pediatric vasculitis causing acquired heart disease.
Purpose of the Study:
- To investigate the role of the NAD+-SIRT1 axis in KD pathogenesis.
- To evaluate therapeutic strategies targeting this axis.
Main Methods:
- Utilized a Lactobacillus casei cell wall extract (LCWE) murine model of KD.
- Assessed vasculitis severity in mice with altered SIRT1 expression or NAD+ precursor supplementation.
- Analyzed autophagy/mitophagy pathways and VSMC switching via proteomics, immunofluorescence, and Western blotting.
- Measured pro-inflammatory cytokine production.
Main Results:
- SIRT1 expression was downregulated in KD lesions.
- NAD+ precursor supplementation or SIRT1 overexpression reduced KD severity.
- Sirt1 deletion in VSMCs or myeloid cells worsened vasculitis.
- SIRT1 overexpression improved mitophagy/autophagy and reduced inflammation.
Conclusions:
- An impaired NAD+-SIRT1 axis contributes to KD vasculitis.
- Targeting the NAD+-SIRT1 axis shows therapeutic potential for KD cardiovascular complications.
