Journal Article

Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis

Karin, Michael, Gomez, Angela C., Lane, Malcolm, Crother, Timothy R., Shimada, Kenichi, Lee, Youngho, Marek-Iannucci, Stefanie, Van Eyk, Jennifer, Porritt, Rebecca A., Zemmour, David, Rivas, Magali Noval, Ozdemir, Asli B., Stotland, Aleksandr, Sanchez-Lopez, Elsa, Gottlieb, Roberta A., Fishbein, Michael C., Moreira, Debbie, Abe, Masanori, Parker, Sarah, Arditi, Moshe

2021

Overview

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: 8-Hydroxy-2'-Deoxyguanosine - blood / 8-Hydroxydeoxyguanosine / Abdomen / Aneurysms / Animal models / Animals / Autophagy / Autophagy - genetics / Autophagy-Related Proteins - genetics / Butanes - pharmacology / Cardiovascular disease / Cell Extracts / Cell Wall / Cell walls / Clonal deletion / Coronary vessels / Coronary Vessels - pathology / Disease Models, Animal / DNA Glycosylases - genetics / Heart diseases / Heart failure / Hypoglycemic Agents - pharmacology / Inflammation / Kawasaki disease / Lactobacillus casei / Lesions / Male / Metformin / Metformin - pharmacology / Mice / Mitochondria / Mitochondrial DNA / Mitophagy / Mitophagy - genetics / Mucocutaneous lymph node syndrome / Mucocutaneous Lymph Node Syndrome - chemically induced / Mucocutaneous Lymph Node Syndrome - genetics / Mucocutaneous Lymph Node Syndrome - pathology / Mucocutaneous Lymph Node Syndrome - physiopathology / Myocardium - pathology / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / OGG1 protein / Organophosphorus Compounds - pharmacology / Pathophysiology / Proteins / Pyridinium Compounds - pharmacology / Reactive Oxygen Species - metabolism / Smooth muscle / Ubiquinone - analogs & derivatives / Ubiquinone - pharmacology / Ubiquitin-Protein Ligases - genetics / Vascular biology / Vasculitis