GSE211656
Sustained increases in cardiomyocyte protein O-GlcNAc levels leads to cardiac hypertrophy and reduced mitochondrial function without systolic contractile impairment
Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease (CVD) through numerous mechanisms, including regulation via post-translational modifications (PTM). A specific PTM, the addition of O-linked ß-N acetylglucosamine (O-GlcNAcylation), has been implicated in both physiological and pathological mechanisms. The current study aimed to test the hypothesis that protein O-GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology when sustained in cardiomyocytes. Using an inducible cardiomyocyte-specific dominant-negative O-GlcNAcase (dnOGAh) overexpression transgenic mouse model, we induced dnOGA in 8-10-weeks-old mouse hearts. We examined the effects of 2-weeks (2wk) and 24-weeks (24wk) dnOGA overexpression, which progressed to a 1.8-fold increase in protein O-GlcNAcylation. 2wk increases in protein O-GlcNAc levels did not alter heart weight or function; however, 24wk increases in protein O-GlcNAcylation led to cardiac hypertrophy, reduced mitochondrial function, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24wk dnOGA overexpression, despite several changes in gene expression associated with CVD. Specifically, mRNA-seq analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid and glucose metabolism pathways, and antioxidant response pathways at 24wk. In contrast, cardiac fibrosis pathway genes were induced at 24wk after dnOGA overexpression. Changes in mitochondrial function after 24wk induction were independent of changes in mitochondrial DNA copy number. This study indicates that moderate protein O-GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2wk phase), which leads to cardiac remodeling (24wk phase) including cardiac hypertrophy, decreased oxidative phosphorylation pathways, and increased cardiac structural changes. This study shows that sustained exposure of elevated protein O-GlcNAcylation in cardiomyocytes alters gene expression and supports a switch to pathophysiological mechanisms of O-GlcNAcylation in adaptive versus maladaptive changes. Overall design: Comparative gene expression analysis of RNA-seq data from left ventricle tissue using Control, cardiac specific overexpressed dominant negative OGA for 2wk induction and 24 week induction.