Transient elevation in cellular glucose uptake exacerbates pressure overload-induced cardiac hypertrophy and...

Area of Science:

• Cardiovascular Science
• Metabolic Disease Research
• Epigenetics

Background:

• Prior hyperglycemia can cause long-term cardiovascular damage, termed 'glycemic memory.'
• Epigenetic modifications, particularly DNA methylation, are hypothesized to mediate this phenomenon.
• Understanding glycemic memory is crucial for preventing heart disease progression.

Purpose of the Study:

• To investigate if prior high glucose exposure exacerbates cardiovascular effects under pressure overload.
• To identify gene expression and DNA methylation signatures associated with glycemic memory in cardiomyocytes.
• To explore potential therapeutic targets for heart failure susceptibility linked to hyperglycemia.

Main Methods:

• Utilized inducible, cardiomyocyte-specific glucose transporter 4 (GLUT4) overexpressing mice.
• Induced high glucose delivery, followed by a return to basal levels, then subjected mice to transverse aortic constriction (TAC) or sham surgery.
• Assessed cardiac function, remodeling, gene expression (RNA-sequencing), and DNA methylation (bisulfite sequencing).

Main Results:

• TAC exacerbated cardiac hypertrophy and dysfunction in high-glucose-exposed mice.
• Persistent molecular changes, including altered gene expression and DNA methylation, were observed even after glucose levels normalized.
• Enriched pathways indicated links between gene expression, DNA methylation, and adverse cardiac events, supporting the glycemic memory concept.

Conclusions:

• Glycemic memory exacerbates cardiac structural and functional decline, mimicking heart failure under secondary stress.
• Identified transcriptome and DNA methylome changes that may serve as molecular signatures of glycemic memory.
• These findings suggest potential therapeutic targets for heart failure resulting from prior hyperglycemia.