Role of HMGB1/TLR4/IL‐33 axis in cardiac myocyte‐fibroblast interaction in the development of diabetic cardiomyopathy

The Objective of the study is to assess HMGB1/TLR4/IL‐33 axis in cardiac myocyte‐fibroblast interaction in the development of diabetic cardiomyopathy. Methods Type I diabetes was induced by streptozotocin in 6‐week male C57BL/6 mice. Myocardial function and fibrosis assessed. In addition, isolated cardiac myocytes and/or fibroblasts were challenged with high glucose (HG) and myocytes‐fibroblasts interaction assessed using a myocyte‐fibroblast co‐culture system. Results In the diabetic mice, myocardial HMGB1 was elevated while IL‐33 was decreased. Further, blockade of the HMGB1/TLR4 pathway prevented the diabetic myocardial 1) decrease in IL‐33 expression, 2) collagen deposition, and 3) dysfunction. In the in vitro model, HG stimulated cardiomyocytes to produce HMGB1. Further, challenge of myocyte/fibroblast co‐cultures with HG indicated that myocyte‐derived HMGB1 decreases fibroblast IL‐33 expression and increases collagen production. Exogenous IL‐33 or over‐expression of IL‐33 prevented the collagen production by fibroblasts. Conclusions the results indicate cardiomyocytes potentiate the collagen production by cardiac fibroblasts under diabetic condition resulting in cardiac dysfunction. Specifically, myocyte HMGB1 decreases fibroblast IL‐33 expression, thereby potentiating their ability to induce myocardial fibrosis and cardiomyopathy. (HSFO NA‐6316; LHRI IRF‐25‐10).