Transient Elevation in Cellular Glucose Uptake Exacerbates Pressure-Overload Induced Cardiac Hypertrophy and Dysfunction

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE275229 | GEO | 2026/03/11

REPOSITORIES: GEO