Abstract
Post-translational modifications (PTMs) of sarcomeric proteins could participate to left ventricular (LV) remodeling and contractile dysfunction leading in advanced heart failure (HF) with altered ejection fraction. Using an experimental rat model of HF (ligation of left coronary artery) and phosphoproteomic analysis, we identified an increase of desmin phosphorylation and a decrease of desmin O-N-acetylglucosaminylation (O-GlcNAcylation). We aim to characterize interplay between phosphorylation and O-GlcNAcylation for desmin in primary cultures of cardiomyocyte by specific O-GlcNAcase (OGA) inhibition with thiamet G and silencing O-GlcNAc transferase (OGT) and, in perfused heart perfused with thiamet G in sham- and HF-rats. In each model, we found an efficiency of O-GlcNAcylation modulation characterized by the levels of O-GlcNAcylated proteins and OGT expression (for silencing experiments in cells). In perfused heart, we found an improvement of cardiac function under OGA inhibition. But none of the treatments either in in vitro or ex vivo cardiac models, induced a modulation of desmin, phosphorylated and O-GlcNAcylated desmin expression, despite the presence of O-GlcNAc moities in cardiac desmin. Our data suggests no interplay between phosphorylation and O-GlcNAcylation of desmin in HF post-myocardial infarction. The future requires finding the targets in heart involved in cardiac improvement under thiamet G treatment.
Highlights
Heart failure (HF) following myocardial infarction (MI) is characterized by alterations of left ventricle (LV) structure and function, known as LV remodeling [1]; this pathophysiological process is a strong predictor of both HF and death as we recently showed in two cohorts of patients REVE and REVE2 dedicated to the analysis of LV remodeling [2, 3]
We looked for interplay between phosphorylation and O-GlcNAcylation of desmin in the same experimental model and found a significant decrease of O-GlcNAcylated desmin in LV of HF rats compared to controls (Figure 1C)
These data showed that desmin may bear O-GlcNAc residues and that the levels of O-GlcNAcylated desmin were inversely related to the levels of phosphorylated desmin in LV of HF rats
Summary
Heart failure (HF) following myocardial infarction (MI) is characterized by alterations of left ventricle (LV) structure and function, known as LV remodeling [1]; this pathophysiological process is a strong predictor of both HF and death as we recently showed in two cohorts of patients REVE and REVE2 dedicated to the analysis of LV remodeling [2, 3]. The long-term (>10 years) clinical follow-up of patients included in these two cohorts has shown that LV remodeling remains independently associated with HF and cardiovascular death [4]
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