title: Cardiomyocyte-fibroblast interaction contributes to diabetic cardiomyopathy in mice: Role of HMGB1/TLR4/IL-33 axis.
abstract: Diabetic cardiomyopathy (DiCM) is characterized by myocardial fibrosis and dysfunction. In rodent models of diabetes myocardial HMGB1 increases while IL-33 decreases. The major cardiac cell type expressing HMGB1 is the myocyte while the primary IL-33 expressing cell is the fibroblast. The aim of this study was to delineate the extracellular communication pathway(s) between cardiomyocytes and fibroblasts that contributes to murine DiCM. The streptozotocin (STZ)-induced murine model of diabetes and a cardiomyocyte/fibroblast co-culture challenged with high glucose were used. In STZ mice, myocardial HMGB1 expression was increased while IL-33 expression decreased (immunofluorescence and Western blot). In addition, STZ mice had an increased myocardial collagen deposition and myocardial dysfunction (pressure-volume loop analysis). An HMGB1 inhibitor (A-box) or exogenous IL-33 prevented the myocardial collagen deposition and dysfunction. In the cardiomyocyte/fibroblast co-culture model, HG increased cardiomyocyte HMGB1 secretion, decreased fibroblast IL-33 expression, and increased fibroblast collagen I production. Further, using A-box and HMGB1 shRNA transfected myocytes, we found that cardiomyocyte-derived HMGB1 dramatically potentiated the HG-induced down-regulation of IL-33 and the increase in collagen I expression in the fibroblasts. The potentiating effects of the cardiomyocytes was diminished when toll-like receptor 4 deficient (TLR4(-/-)) fibroblasts were co-cultured with wild-type myocytes. Finally, TLR4(-/-) mice with diabetes had increased myocardial expression of HMGB1, but failed to down-regulate IL-33. The diabetes-induced myocardial collagen deposition and cardiac dysfunction were significantly attenuated in TLR4(-/-) mice. In conclusion, our findings support a role for "cardiomyocyte HMGB1-fibroblast TLR4/IL-33 axis" in the development of myocardial fibrosis and dysfunction in a murine model of diabetes.
authors.affiliation: Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, PR China; Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Aibin
authors.initials: A
authors.lastname: Tao
authors.affiliation: Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Song
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Ting
authors.initials: T
authors.lastname: Lan
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Physiological Sciences, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kvietys
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; Critical Care Western, University of Western Ontario, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kao
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; Critical Care Western, University of Western Ontario, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Claudio
authors.initials: C
authors.lastname: Martin
authors.affiliation: Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, PR China; Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada; Critical Care Western, University of Western Ontario, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. Electronic address: trui@uwo.ca.
authors.forename: Tao
authors.initials: T
authors.lastname: Rui
keywords: Diabetes mellitus; HMGB1; IL-33; Myocardial fibrosis; TLR4