The role of HMGB1 in diabetic cardiomyopathy

Aims: Increasing evidence has established causative links between chronic inflammation and insulin resistance and type 2 diabetes mellitus. The aim of this study is to evaluate the role of High-mobility group box 1 (HMGB1), a potent innate “danger signal”, in the induction and propagation of a chronic inflammatory response in an animal model of diet induced obesity/type 2 diabetes (DIO) alone and in combination with chronic pressure overload induced hypertrophy after transverse aortic constriction (TAC).

Results: Diabetic environment alone led to the activation of isolated cardiomyocytes, cardiac fibroblasts and macrophages in an HMGB1-RAGE dependent way. In addition, DIO induced a sustained HMGB1 expression in the myocardium on both RNA (p < 0.01) and protein level (p < 0.0001) in comparison to healthy control mice up to 16 weeks. Furthermore, DIO lead to deterioration in cardiac fractional shortening (FS; p > 0.05) and to cardiomyocyte hypertrophy (p > 0.05) compared to untreated controls. To investigate whether the receptor for advanced glycation endproducts (RAGE) contributes to HMGB1-mediated deterioration of myocardial function, DIO was induced in RAGE^-/-. Decrease of FS and cardiomyocyte hypertrophy were significantly blunted in RAGE^-/- mice with DIO compared to wild-type (WT) mice with DIO. If in addition to DIO mice were treated with TAC, decrease of FS (p < 0.05) and cardiac hypertrophy (p < 0.05) were significantly attenuated in RAGE^-/- mice compared to WT mice. To validate if the activation of RAGE by HMGB1 accounts for the deterioration of cardiac function, WT mice with DIO and TAC were treated with HMGB1 antagonist HMGB1 box A (box A). Box A treatment significantly reduced remodeling in WT DIO mice with TAC compared to the untreated control group (p < 0.05). Furthermore, in the DIO+TAC group box A improved the recovery of cardiac function (p < 0.001) compared to the control group. Signalling studies in isolated left ventricles from box A treated WT mice (DIO+TAC) demonstrated decreased phosphorylation of the ERK1/2 (p < 0.0002) and JNK (p < 0.0002) but not of the p38 MAP-kinases. Furthermore box A treated animals and RAGE^-/- mice displayed significantly reduced levels of apoptosis in this cardiac stress model.

Conclusion: We propose that HMGB1 is a key component in the initiation and development of diabetic cardiomyopathy thus representing a potential new therapeutic target.