Targeting the SIRT1 pathway to modulate inflammation in a murine model of Kawasaki Disease vasculitis

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Presentation Time: 04:30 PM - 04:45 PM
Abstract ID: 4220 - B

Presenting Author:
Asli E. Atici , Postdoctoral Scientist at Cedars-Sinai Med. Ctr.

Abstract:

Kawasaki Disease (KD) is an acute febrile systemic vasculitis and the leading cause of acquired heart disease among children. Overactivation of the NLRP3 inflammasome and IL-1b production are critical for the development of cardiovascular lesions during KD. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylase, is crucial for responding to cellular stress, and regulates NLRP3 activation as well as clearance of damaged mitochondria in cardiovascular diseases. However, its role in KD pathophysiology remains unknown. Here, we used the Lactobacillus casei cell wall extract (LCWE) murine model of KD to determine the role of SIRT1 on the development of cardiovascular lesions. We show that Sirt1 expression is downregulated in LCWE-injected mice with a significant reduction of nicotinamide, a product resulting from NAD⁺ degradation by SIRT1. In addition, supplementation of mice with NAD⁺ precursors significantly reduced the development of LCWE-induced cardiovascular lesions. Furthermore, KD development was less severe in SIRT1 overexpressing mice but was exacerbated with the specific deletion of Sirt1 in vascular smooth muscle cells. Treatment of LCWE-stimulated coronary smooth muscle cells with a SIRT1 activator favored mitophagy by inhibiting ribosomal S6 phosphorylation. These results indicate an impaired NAD⁺/SIRT1 axis during LCWE-induced KD vasculitis, which could potentially be targeted to reduce cardiovascular lesions in KD.