Sustained Increases in Cardiomyocyte Protein O‐Linked β‐N‐Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment

Background Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease through numerous mechanisms, including regulation via posttranslational modifications. A specific posttranslational modification, the addition of O‐linked β‐N acetylglucosamine (O‐GlcNAcylation), has been implicated in molecular mechanisms of both physiological and pathologic adaptations. The current study aimed to test the hypothesis that in cardiomyocytes, sustained protein O‐GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology. Methods and Results Using a naturally occurring dominant‐negative O‐GlcNAcase (dnOGA) inducible cardiomyocyte‐specific overexpression transgenic mouse model, we induced dnOGA in 8‐ to 10‐week‐old mouse hearts. We examined the effects of 2‐week and 24‐week dnOGA overexpression, which progressed to a 1.8‐fold increase in protein O‐GlcNAcylation. Two‐week increases in protein O‐GlcNAc levels did not alter heart weight or function; however, 24‐week increases in protein O‐GlcNAcylation led to cardiac hypertrophy, mitochondrial dysfunction, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24‐week dnOGA overexpression, despite several changes in gene expression associated with cardiovascular disease. Specifically, mRNA‐sequencing analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid, and glucose metabolism pathways, and antioxidant response pathways after 24‐week dnOGA overexpression. Conclusions This study indicates that moderate increases in cardiomyocyte protein O‐GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2‐week), which leads to cardiac remodeling (24‐week). Moreover, the mouse model showed evidence of diastolic dysfunction consistent with a heart failure with preserved ejection fraction. These findings provide insight into the adaptive versus maladaptive responses to increased O‐GlcNAcylation in heart.