Roles of Oxidative Injury and Nitric Oxide System Derangements in Kawasaki Disease Pathogenesis: A Systematic Review

Figures

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  Figure 1. Major clinical features of Kawasaki disease.

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  Figure 2. Etiology and pathophysiology of vascular endothelial dysfunction in Kawasaki disease. Kawasaki disease is triggered by various factors, such as genetic predisposition and infectious and environmental triggers. Oxidative stress and systemic inflammation are induced in the acute phase through both the innate immune response and adaptive immune response. These lead to endothelial dysfunction and long-term cardiovascular complications, such as coronary artery stenosis, occlusion, and/or thrombosis. Abbreviations: DAMPs, damage-associated molecular patterns; LMW, low molecular weight; PAMPs, pathogen-associated molecular patterns.

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  Figure 3. Kawasaki disease and multisystem inflammatory syndrome in children (MIS-C). Abbreviations: KD, Kawasaki disease; KDSS, Kawasaki disease shock syndrome; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

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  Figure 4. Metabolic network centered on L-arginine. In the physiological state, arginine is regenerated from citrulline via “citrulline–arginine recycling” in the blood vessel and the kidney, and the vascular endothelial cells can maintain NO synthesis via this pathway. In inflammatory pathologies (increased oxidative stress status), arginase is induced in many cells, such as the blood vessels and macrophages, and NO synthesis derived from the vascular endothelium decreases through the “arginine steal phenomenon”. The increased catabolism of arginine via arginase may not only compromise the ability to synthesize NO constitutively but may also increase the production of ornithine, a precursor for the synthesis of proline and polyamines required for cell proliferation and collagen synthesis. ADMA, asymmetric dimethylarginine; ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; DDAH, dimethylarginine dimethylaminohydrolase; NO, nitric oxide; NOS, nitric oxide synthase; OTC, ornithine transcarbamylase. Reprinted by permission from the journal “Antioxidants”.

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  Figure 5. L-arginine-NOS-NO pathway versus PRMT-ADMA-DDAH pathway. Note that ROS enhance the activity of PRMT and that the action of DDAH is suppressed by ROS (or high levels of NO). Notably, endothelial NOS (NOS3) is suppressed by ROS (or high levels of NO). Thus, oxidative stress enhancement and endothelial NOS inhibition play pivotal roles in cardiovascular pathologies by regulating PRMT/DDAH activity and NO synthesis, leading to “endothelial dysfunction”. ADMA, asymmetric dimethylarginine; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; CAAT, cationic amino acid transporter; DDAH, dimethylarginine dimethylaminohydrolase; NO, nitric oxide; NOS, nitric oxide synthase; PRMT, protein arginine methyltransferase; ROS, reactive oxygen species.

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  Figure 6. Perspective on the clinical use of oxidative stress biomarkers. Abbreviations: CML, carboxymethyl lysine; CSF, cerebrospinal fluid; HNE, 4-hydroxy-2-nonenal; MDA, malondialdehyde; 8-OHdG, 8-hydroxy-2′-deoxyguanosine. Only the representative markers are presented here.

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  Figure 7. Enterosalivary nitrate-nitrite-NO pathway.