Induction of autophagy or mitophagy improves the cardiovascular lesions of Kawasaki Disease in a murine model of vasculitis

Abstract

Abstract Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. NLRP3 activation and IL-1 signaling are required for the development of coronary arteritis and abdominal aorta aneurysms (AAA) in the KD vasculitis murine model. NLRP3 is also activated by mitochondrial (mt) DNA released from impaired mitophagy-autophagy processes. How autophagy and mitophagy participate in KD cardiovascular lesions remain unknown. We investigated the role of autophagy/mitophagy by using the well-accepted Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis. LCWE injection in WT mice results in coronary arteritis, aortitis, myocarditis as well as AAA. p62 and Parkin, were expressed significantly higher in whole lysate and mt fractions of cardiovascular tissues from LCWE-injected mice compared to control, suggesting an impaired autophagic flux and lack of degradation and cell clearance. Parkin−/− mice developed significantly higher LCWE-mediated cardiovascular lesions and AAA, compared to control mice. Conversely, autophagy induction in WT mice by intermittent fasting or by treatment with a Glucagon-like peptide-1 receptor agonist, led to a significant decrease in LCWE-mediated cardiovascular lesions and AAA. This data suggests that induction of autophagy leads to decreased cardiovascular lesions, whereas impaired mitophagy results in exacerbation of LCWE-induced cardiovascular lesions in this murine model of KD vasculitis. These findings enhance our understanding of the pathogenesis of the cardiovascular lesions in KD vasculitis and may provide novel therapeutic targets to prevent or treat these complications.