Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis
Stefanie Marek-Iannucci, Asli B. Ozdemir, Debbie Moreira, Angela C. Gomez, Malcolm Lane, Rebecca A. Porritt, Youngho Lee, Kenichi Shimada, Masanori Abe, Aleksandr Stotland, David Zemmour, Sarah Parker, Elsa Sanchez-Lopez, Jennifer Van Eyk, Roberta A. Gottlieb, Michael C. Fishbein, Michael Karin, Timothy R. Crother, Magali Noval Rivas, Moshe Arditi
Stefanie Marek-Iannucci, Asli B. Ozdemir, Debbie Moreira, Angela C. Gomez, Malcolm Lane, Rebecca A. Porritt, Youngho Lee, Kenichi Shimada, Masanori Abe, Aleksandr Stotland, David Zemmour, Sarah Parker, Elsa Sanchez-Lopez, Jennifer Van Eyk, Roberta A. Gottlieb, Michael C. Fishbein, Michael Karin, Timothy R. Crother, Magali Noval Rivas, Moshe Arditi
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Research Article Inflammation Vascular biology

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

Abstract

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.

Authors

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

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Figure 5

ROS and oxidative DNA damage activate NLRP3 and influence cardiovascular lesion formation.

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ROS and oxidative DNA damage activate NLRP3 and influence cardiovascular...
(A) 8-OHdG levels measured in serum of PBS- or LCWE-injected WT mice 1 week after injection (n = 9–11/group). (B) Representative dihydroethidium (DHE) staining and ROS quantification in frozen abdominal aorta tissue cross-sections collected from WT mice injected wither with PBS or LCWE 1 week after injection (n = 5–6/group). Scale bars: 100 µm. (C) Heart sections H&E staining and heart vessel inflammation score of LCWE-injected WT (n = 8) and Ogg1–/– mice (n = 9) 1 week after LCWE injection. Scale bars: 500 µm. (D) Representative pictures of the abdominal aorta, maximal aorta diameter, and abdominal aorta area measurements from LCWE-injected WT (n = 8) and Ogg1–/– (n = 9) mice at 1 week after injection. (E) FLICA staining and quantification in frozen heart tissue sections of LCWE-injected WT and Ogg1–/– mice at 1 week after LCWE injection (n = 5/group). White arrows indicate FLICA+ cells. Scale bars: 100 µm. (F) Representative DHE staining and ROS quantification in abdominal aorta tissue cross-sections from LCWE-injected WT and Ogg1–/– mice, 1 week after injection (n = 7/group). Scale bar: 100 µm. (G) Heart sections shown with H&E staining and heart vessel inflammation score of WT mice injected with LCWE or WT mice injected with LCWE and MitoQ 1 week after LCWE injection (n = 10/group). Scale bars: 500 µm. (H) Representative pictures of the abdominal aorta area, maximal aorta diameter, and measurements of the abdominal aorta area from LCWE-injected WT mice and WT mice injected with LCWE and MitoQ 1 week after LCWE injection (n = 10/group). (I) Representative DHE staining and ROS quantification in abdominal aorta tissue cross-sections collected from WT mice injected with LCWE or WT mice injected with LCWE and MitoQ 1 week after injection (n = 5/group). Scale bar: 100 µm. (J) 8-OHdG levels measured in the serum of WT mice treated with LCWE + PBS or LCWE + MitoQ 1 week after injection (n = 5–7/group). *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired Student t tests.