Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Ha CM

PROVIDER: S-EPMC10727241 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ha Chae-Myeong CM Bakshi Sayan S Brahma Manoja K MK Potter Luke A LA Chang Samuel F SF Sun Zhihuan Z Benavides Gloria A GA He Lihao L Umbarkar Prachi P Zou Luyun L Curfman Samuel S Sunny Sini S Paterson Andrew J AJ Rajasekaran Namakkal-Soorappan NS Barnes Jarrod W JW Zhang Jianhua J Lal Hind H Xie Min M Darley-Usmar Victor M VM Chatham John C JC Wende Adam R AR

Journal of the American Heart Association 20230926 19

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, sustaine ...[more]

PMID: 37750556

Similar Datasets

Project description: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 β-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.

Project description:Adaptation of gene expression is one of the most fundamental response of cardiomyocytes to hypertrophic stimuli. G3bp1, an RNA binding protein with site-specific endoribonuclease activity regulates the processing of pre-miR-1 stem-loop, and thus levels of cardiomyocyte -enriched mature miR-1. Here, we examine the role of G3bp1 in regulating gene expression in quiescent cardiomyocytes and those undergoing growth-factor induced hypertrophy. Further, we determine if these changes are facilitated through G3bp1-mediated regulation of miR-1 in these cardiomyocytes. Using isolated cardiomyocytes with knockdown of endogenous G3bp1, we performed high throughput RNA sequencing to determine the change in cardiac transcriptome. Then, using gain and loss of function approach for both, G3bp1 and miR-1, alone or in combination we examine the G3bp1-miR-1 signaling in regulating gene expression and Endothelin (ET-1) -induced cardiomyocyte hypertrophy. We show that knockdown of endogenous G3bp1 results in inhibition of genes involved in calcium handling, cardiac muscle contraction, action potential and sarcomeric structure. In addition, there is inhibition of genes that contribute to hypertrophic and dilated cardiomyopathy development. Conversely, an increase is seen in genes that negatively regulate the Hippo signaling, like Rassf1 and Arrdc3, along with inflammatory genes of TGF-β and TNF pathways. Knockdown of G3bp1 restricts ET-1 induced cardiomyocyte hypertrophy. Interestingly, concurrent silencing of G3bp1 and miR-1 rescues the change in gene expression and inhibition of hypertrophy seen with knockdown of G3bp1 alone. Similarly, expression of exogenous G3bp1 reverses the miR-1 induced inhibition of gene expression. Intriguingly, expression of Gfp tagged G3bp1 results in perinuclear accumulations of G3bp1-Gfp, resembling Stress Granules. Based on our results, we conclude that G3bp1 through its regulation of mature miR-1 levels plays a critical role in regulating the expression of essential cardiac-enriched genes and those involved in development of cardiomyocyte hypertrophy.

Dataset Information

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

Publications

Sustained Increases in Cardiomyocyte Protein <i>O</i>-Linked β-N-Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Publications

Sustained Increases in Cardiomyocyte Protein &lt;i&gt;O&lt;/i&gt;-Linked β-N-Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sustained Increases in Cardiomyocyte Protein <i>O</i>-Linked β-N-Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment.