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. 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.