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

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.