Aim: 

Heart failure is a leading cause of morbidity and mortality in the Western world, yet the underlying signaling processes in the heart are not well known. Post-translational modifications of cardiac proteins are important for cardiovascular function, e.g. protein phosphorylation has been widely studied. O-GlcNAcylation is another such reversible protein modification that has emerged as an essential signaling mechanism in several tissues. Currently, there is limited knowledge about O-GlcNAc signaling in the heart, and we tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies.

Methods: 

Cardiac protein O-GlcNAcylation and the two enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), were measured by immunoblotting left ventricular tissue from aortic stenosis (AS) patients and rat models of myocardial infarction (MI), hypertension and aortic banding (AB). Echocardiography, hemodynamic evaluation and post-mortem analysis were used to separate heart failure from non-failing cardiac hypertrophy.

Results: 

We show that cardiac protein O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81% and 58% after AB and 37% and 60% after MI in hypertrophic and failing hearts, respectively. Noticeable, protein O-GlcNAcylation patterns varied in hypertrophic versus failing hearts. OGT levels were increased by pressure overload (AS, AB, hypertension), while OGA was increased in AS and AB. Neither OGT nor OGA levels were regulated by myocardial infarction.

Conclusion: 

Our data demonstrate that O-GlcNAcylation of cardiac proteins, a novel concept in cardiac signaling, is dramatically altered in AS patients and rat models of cardiac hypertrophy and failure of different etiologies. Although the functional consequences remain unclear, and the specific protein targets are unknown, these results represent an exciting basis for research aiming to understand the molecular mechanisms of heart disease.