Transient Increase in Cardiomyocyte Protein O-GlcNAcylation Enhances Susceptibility to Pressure Overload-Induced...

The observation that patients with diabetes always under tight-glycemic control consistently show better cardiovascular disease outcomes compared with patients who transition to tight-glycemic control after prior conventional glycemic control led to the concept of metabolic memory. Mechanisms such as epigenetics possibly mediate the lasting metabolic memory effects, without a known mechanism. Increased cardiac protein posttranslational O-linked β-N-acetylglucosamine (O-GlcNAc) modification is implicated in cardiac remodeling observed in diabetes, and our previous work shows that chronically elevated cardiomyocyte O-GlcNAc causes adverse cardiac changes. We hypothesized that transiently increased cardiomyocyte O-GlcNAcylation leads to exacerbated adverse cardiac remodeling after subsequent pressure-overload.

Using an inducible cardiomyocyte specific, dominant-negative O-GlcNAcase (dnOGAh) mouse and single transgenic littermate controls (Con), we induced O-GlcNAc levels for 2 weeks (ON), followed by a 2-week washout (OFF); mice then underwent transverse-aortic constriction (TAC) or Sham surgery followed by comprehensive physiological and molecular assessments.

We observed the expected cardiac remodeling in TAC groups, including decreased cardiac function, and increased hypertrophy and fibrosis. Moreover, these pathologic measures were exacerbated in the ON/OFF-TAC versus Con-TAC mice; additionally, transcriptomic analysis of left ventricle tissue from each experimental group showed pathways which supported our fibrosis, hypertrophy and functional results of exacerbated cardiac remodeling, and revealed potential novel molecular pathways underlying this pathologic remodeling.

We observed exacerbated cardiac pathology between ON/OFF-TAC versus 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.