Disruption of the Clock O-GlcNAc axis in diabetic cardiomyopathy

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DESCRIPTION (provided by applicant): Diabetes remains a major risk factor for the development of both ischemic and non-ischemic cardiovascular disease (CVD); however, despite improvements in clinical treatments, our knowledge of the molecular underpinnings of diabetes-associated CVD is poorly understood. As with the majority of cardiovascular physiology, pathologic cardiovascular events exhibit a time-of-day-dependence, with regards to both onset and impact on disease progression and we have shown that the cardiomyocyte circadian clock directly influences the manner with which the heart responds to specific stressors. Importantly, we have shown that diabetes induces a phase shift in the cardiomyocyte circadian clock. Thus dysynchrony of the cardiomyocyte circadian clock may be an important and previously unrecognized contributor to the etiology of diabetic cardiomyopathy. Protein O-GlcNAcylation, a metabolically regulated post-translational modification that rapidly influences protein function, is increasingly recognized as a key regulator of both cardiac physiology and pathology including the adverse effects of diabetes. We recently reported that the cardiomyocyte circadian clock directly influences cardiac O-GlcNAc levels, that at least two circadian clock components are O-GlcNAc modified, and those acute increases in O-GlcNAc levels phase shifts the clock similarly to that seen in the heart during diabetes. We have also observed increased protein synthesis in the heart during the inactive phase, a time when protein O-GlcNAcylation is low. This has led us to postulate that protein O- GlcNAcylation may be a key mechanism by which the cardiomyocyte circadian clock temporally coordinates repair/replacement of damaged proteins in the heart. Collectively, these observations support the overall hypothesis of this proposal that dysregulation of protein O-GlcNAcylation is a critical factor contributing to diabetes-induced alterations of the cardiomyocyte circadian clock, and that misalignment of the cardiomyocyte circadian clock represents a key mechanism underlying diabetes-related cardiac dysfunction. To test this hypothesis we will pursue 3 specific aims: 1) Determine the molecular underpinnings linking the cardiomyocyte circadian clock with protein O-GlcNAcylation, and identify how this relationship is altered during diabetes; 2) Determine the role of O-GlcNAcylation in circadian clock mediated protein turnover, and elucidate how this relationship is modified during diabetes; 3) Determine whether re-alignment of the cardiomyocyte circadian clock during diabetes attenuates cardiomyopathy development. Successful completion of the proposed studies will lead to new fundamental insights regarding the molecular mechanisms underlying the role of aberrant circadian function in the development of diabetes-related cardiac disease and will help identify new approaches for reducing the risk of CVD in diabetic patients.