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A Transient Increase in Cardiomyocyte Protein O-GlcNAcylation Enhances Susceptibility to Pressure Overload-Induced Cardiac Remodeling

ABSTRACT: The concept of metabolic memory comes from findings that diabetic patients always under tight-glycemic control consistently show better cardiovascular disease outcomes compared to patients who transition to tight-glycemic control after prior conventional glycemic control; mechanisms like epigenetics possibly mediate the lasting metabolic memory effects, however more research into underlying mechanisms is needed. Within the diabetic milieu, increased cardiac protein posttranslational O-linked β-N-acetylglucosamine (O-GlcNAc) modification is implicated in cardiac remodeling, and our previous work shows chronically elevated cardiac O-GlcNAc causes adverse cardiac changes. Therefore, the current study hypothesized that transiently increased cardiomyocyte O-GlcNAcylation leads to exacerbated adverse cardiac remodeling after subsequent pressure-overload. Using our previously described inducible cardiomyocyte specific, dominant-negative O-GlcNAcase (dnOGAh) mouse or single transgenic littermate controls (Con), we induced O-GlcNAc levels for 2wk (ON), followed by a 2wk washout (OFF); mice then underwent transverse-aortic constriction (TAC) or Sham surgery. We observed the expected cardiac remodeling in TAC groups, like decreased cardiac function, and increased hypertrophy and fibrosis. However, we see exacerbation of these pathologic measures in the ON/OFF-TAC vs. Con-TAC mice; additionally, transcriptomic analysis of LV-tissue from each experimental group showed pathways which not only supported phenotypic results of furthered cardiac remodeling, but also, revealed potential novel molecular pathways underlying this pathologic remodeling. We observed exacerbated cardiac pathology between ON/OFF-TAC vs. Con-TAC groups supporting the concept of “O-GlcNAc memory” as a component of metabolic memory. Moreover, transcriptomic analysis provides insight into potential molecular pathways underpinning this metabolic/O-GlcNAc memory such as Ccn2/CTGF driven fibrosis, and/or Nox4 driven oxidative stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE298401 | GEO | 2026/06/12

REPOSITORIES: GEO

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			Action	DRS
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	GSE298401_dnOGA_ONOFFTAC_RNASeq_Norm_Counts.xlsx	Xlsx

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Project description:BACKGROUND: Clinical studies support that prior hyperglycemia can lead to long-lasting adverse cardiovascular effects, referred to as “glycemic memory”. Several studies support that epigenetic modifications, specifically DNA methylation changes, influenced by altered metabolic pathways, may play a key role in this phenomenon. The objective of this study was to ascertain the gene expression and corresponding DNA methylation signatures linked to glycemic memory, and to investigate if these changes, in long-term, lead to worsened cardiovascular effects upon pressure overload. METHODS AND RESULTS: Using inducible and cardiomyocyte specific GLUT4 overexpression transgenic mice, we induced glucose delivery for 2 weeks, followed by another 2 weeks of basal uptake. Next, we employed RNA-sequencing and reduced representation bisulfite sequencing and discovered differential gene expression and DNA methylation signatures that persisted even after cellular glucose levels reverted to normal. Significant changes across both expression and methylation enriched pathways associated with adverse cardiac events, indicating a potential glycemic memory response. To understand the long-term effects of these changes, we also performed sham or transverse aortic constriction (TAC) surgery at this four-week timepoint to induce pressure overload-mediated secondary stress. Mice were then followed for an additional 8 weeks and assessed for contractile function by echocardiography, cellular remodeling, and molecular analysis. Pressure overload led to an exacerbated hypertrophic response and cardiac dysfunction. Subsequent qPCR-mediated expression analysis identified molecular changes akin to heart failure, worsened cardiac fibrosis, and impaired oxidative stress. CONCLUSIONS: These results indicate an altered transcriptome and DNA methylome upon prior transient enhanced glucose delivery, which evokes a glycemic memory response, responsible for long-term heart failure predisposition. We also identified molecular signatures of differential expression and methylation, as well as potential hubs that may provide novel targets for mechanistic understanding and therapeutic interventions.

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A Transient Increase in Cardiomyocyte Protein O-GlcNAcylation Enhances Susceptibility to Pressure Overload-Induced Cardiac Remodeling

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