Abstract 1585: The Role of Hmgb1 in the Development of Diabetic Cardiomyopathy
We studied the impact of High-mobility group box 1 (HMGB1), a newly recognized innate danger signal for the initiation of host defense and tissue repair, and the receptor for advanced glycation endproducts (RAGE) on the pathogenesis of early and late phase complications of diabetic cardiomyopathy in an animal model of type 1 diabetes mellitus (DM) with myocardial ischemia /reperfusion (I/R). DM alone induced enhanced HMGB1 expression in the myocardium on both RNA (n=10, p<0.01) and protein level (n=10, p<0.0001) in comparison to healthy control mice up to 10 weeks. The diabetic environment alone led to histological signs of remodeling such as myocyte hypertrophy, mononuclear cell infiltration and interstitial fibrosis. Diabetic animals which were subjected to I/R injury (DM+I/R) compared to the groups with I/R or diabetes alone (DM) displayed significantly pronounced cardiac remodeling assessed in a fibrosis score (n=10, p<0.001) next to an enhanced proinflammatory response in the reperfused left ventricles shown by increased TNF-α (n=10, p<0.001) and IL-6 (n=10, p<0.001) RNA leveles. To investigate whether RAGE contributes to HMGB1-mediated injury in the myocardium, wild-type (WT) and RAGE−/− mice were treated with HMGB1 antagonist HMGB1 box A (box A). Box A treatment significantly reduced remodeling and inflammation in diabetic WT mice with I/R injury compared to the untreated control group (n=10, p<0.001). Furthermore, in the DM+ I/R group box A drastically improved the survival rate (n=20, p<0.005) and recovery of cardiac function (n=10, p<0.0001), compared to control group. In contrast, RAGE−/− mice with I/R and DM displayed only slight remodeling (n=10, p< 0.0001) and inflammation (n=10, p<0.0002) along with better cardiac performance (44±1.2 vs 29±5.3, n=10, p<0.0001) compared to the WT controls which was not blunted by box A treatment. Signaling studies in isolated left ventricles from box A treated WT mice (DM+I/R) demonstrated decreased phosphorylation of the MAP-kinases ERK1/2 (n=10, p<0.0002) and JNK (n=10,<0.0002) but not p38. We propose that HMGB1/RAGE-interaction is a key component initiating and sustaining an inflammatory response following ischemic stress eventually leading to the development of diabetic cardiomyopathy.