Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy

Area of Science:

• Cardiovascular Biology
• Metabolic Regulation
• Molecular Cardiology

Background:

• Pressure overload triggers complex myocardial responses involving metabolic cues like O-GlcNAc.
• Elevated O-GlcNAc promotes cardiomyocyte hypertrophy in vitro, but its in vivo role remains unclear.

Purpose of the Study:

• To investigate the role of O-GlcNAc transferase (OGT) in cardiomyocyte hypertrophy and heart failure in vivo.
• To determine if OGT deficiency impacts cardiac function under pressure overload.

Main Methods:

• Utilized patient samples and a preclinical mouse model (i-cmOgt-/- mice) with cardiomyocyte-specific OGT deletion.
• Subjected mice to transverse aortic constriction to induce pressure overload.
• Analyzed myocardial tissue for O-GlcNAcylation, hypertrophy, fibrosis, and metabolic/signaling pathways.

Main Results:

• Increased O-GlcNAcylation in heart failure patients.
• OGT deletion exacerbated ventricular dysfunction post-pressure overload without significant metabolic transcript changes.
• No histological differences in hypertrophy or fibrosis, but elevated cardiomyocyte dedifferentiation markers in OGT-deficient cells.

Conclusions:

• Cardiomyocyte OGT is not required for hypertrophy in vivo.
• Loss of OGT may induce subtle cardiomyocyte phenotypic changes, increasing susceptibility to pressure overload-induced dysfunction.