| Autor: |
Ha CM; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Bakshi S; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Brahma MK; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Potter LA; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Chang SF; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Sun Z; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Benavides GA; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., He L; Division of Cardiovascular Disease, Department of Medicine University of Alabama at Birmingham Birmingham AL., Umbarkar P; Division of Cardiovascular Disease, Department of Medicine University of Alabama at Birmingham Birmingham AL., Zou L; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Curfman S; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Sunny S; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Paterson AJ; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine University of Alabama at Birmingham Birmingham AL., Rajasekaran NS; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Barnes JW; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham Birmingham AL., Zhang J; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Lal H; Division of Cardiovascular Disease, Department of Medicine University of Alabama at Birmingham Birmingham AL., Xie M; Division of Cardiovascular Disease, Department of Medicine University of Alabama at Birmingham Birmingham AL., Darley-Usmar VM; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Chatham JC; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL., Wende AR; Division of Molecular and Cellular Pathology, Department of Pathology University of Alabama at Birmingham Birmingham AL. |
| Abstrakt: |
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. |
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