Project Summary / Abstract Heart failure (HF), the end-result of pathological cardiac remodeling, is a leading cause of death worldwide. As such, it is responsible for a huge societal burden of morbidity, mortality, and cost. Numerous events contribute to the rise in HF, but the increasing prevalence of diabetes is an important contributor. The majority of patients with diabetes succumb ultimately to heart disease, much of which stems from atherosclerotic disease and hypertension. However, cardiomyopathy can develop independent of elevated blood pressure or coronary artery disease, a process termed diabetic cardiomyopathy. We recently elucidated a previously unrecognized signaling axis linking FoxO activation and shifts in metabolic substrate utilization, cardiomyocyte insulin resistance, myocyte steatosis, and the cardiomyopathic phenotype. Further, we have identified metabolic stress-induced down-regulation of IRS1 as the molecular site of FoxO1-elicited insulin resistance. Together, these data uncover previously unrecognized FoxO1-dependent negative feedback in the regulation of insulin signaling and implicate FoxO1 activation in the pathogenesis of diabetic cardiomyopathy. Here, we propose to define cardiomyocyte-autonomous mechanisms of diabetic cardiomyopathy. Already, we have performed preliminary studies that support the hypothesis that persistent activation of the transcription factor FoxO1 is a significant driver of cardiomyocyte insulin resistance and ultimately failure. Beyond that, we and others have collected evidence pointing to an important role of a group of enzymes known as histone deacetylases (HDACs) as integrators of the complex signaling cascades activated during cardiac stress, leading us to further hypothesize that the inhibition of HDAC activity will lead to the attenuation of diabetic cardiomyopathy. Aim 1: Determine mechanisms of FoxO-driven cardiomyopathy in diabetes. We have designed a series of experiments to elucidate molecular events underlying stress-induced, FoxO1-dependent cardiomyopathy. Aim 2: To determine mechanisms of FoxO-dependent inactivation of IRS1. We propose to unveil molecular events linking FoxO transcriptional activity and IRS1 phosphorylation. Aim 3: To examine the role of HDAC inhibition in attenuating FoxO-driven cardiomyopathy in diabetes. We have preliminary evidence that HDAC inhibition can restore insulin responsiveness in animals exposed to a high fat diet (HFD). Here, we will examine the role of HDACs in the cardiac response to HFD. Our findings suggest that FoxO1 – a molecule situated at the nexus of multiple forms of cardiac plasticity – has novel therapeutic relevance in diabetic cardiomyopathy. Further, we have collected evidence suggesting that inhibition of HDAC activity can ameliorate the heart's response to metabolic stress. We will define the mechanisms and functional relevance of these molecular pathways in diabetic heart disease.