Dysfunction of mitochondria and deformed gap junctions in the heart of IL-18-deficient mice

• Published in: American journal of physiology. Heart and circulatory physiology 2016-08, Vol.311 (2), p.H313-H325
• Main Authors: Li, Wen, Jin, Denan, Hata, Masaki, Takai, Shinji, Yamanishi, Kyosuke, Shen, Weili, El-Darawish, Yosif, Yamanishi, Hiromichi, Okamura, Haruki
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - genetics; Blotting, Western; Cardiology; Cardiomyocytes; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cells, Cultured; Connexin 43 - metabolism; Cytokines; Echocardiography; Electron Transport Complex I - metabolism; Electron Transport Complex IV - metabolism; Gap Junctions - ultrastructure; Interferon; Interleukin-18 - genetics; Interleukin-18 - pharmacology; Male; Mice; Mice, Knockout; Microscopy, Electron; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria, Heart - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - ultrastructure; Phosphoproteins - metabolism; Phosphorylation; Physical Endurance; Physiology; Reactive Oxygen Species - metabolism; Rodents; Systole; Up-Regulation
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00927.2015

Interleukin-18 (IL-18) was discovered as an interferon-γ-inducing factor and has been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in nonimmune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18KO mice ran significantly shorter distances compared with wild-type (WT) mice. Echocardiographs indicated disability in the systolic and diastolic functions of the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous localization of gap junctions in the lateral membranes of the IL-18KO cardiac myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 in the IL-18KO heart. Electron microscopy revealed unusual localization of intercalated disks, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphological observation, mitochondrial respiratory function, including that of complexes I and IV, was impaired, and production of reactive oxygen species was augmented in IL-18KO hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous IL-18 upregulated LC3-II and increased the number of intact mitochondria with high mitochondrial membrane potential. These results indicated that IL-18 has roles apart from those as a proinflammatory cytokine in cardiac myocytes and suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial function and gap-junction turnover in cardiac myocytes, possibly by upregulating autophagy.