Abstract 3549: O-GlcNAc Transferase Is Indispensable in Heart Failure
Background and Hypothesis: The O-linked beta-N-acetylglucosamine (O-GlcNAc) post-translational modification integrates glucose metabolism with intracellular protein activity and localization. During heart failure (HF), a metabolic shift from free fatty acids to glucose occurs. Because O-GlcNAc is derived from glucose, we hypothesized that altered O-GlcNAc signaling would occur and figure prominently in HF pathophysiology.
Methods and Results: We subjected wild-type mice to coronary ligation (HF) or sham (‘n’ values shown in figure⇓). After five days, cardiac O-GlcNAc transferase (OGT, which adds O-GlcNAc to proteins) and O-GlcNAc levels were significantly elevated (p<0.05; Panels A & B). We used the MerCreMer transgene (Tg) system, coupled with loxP-flanked OGT mice, to develop inducible, cardiac myocyte specific OGT ‘knockouts’. After tamoxifen induction, cardiac OGT levels were significantly (p< 0.05) reduced compared to NTg (Panel C), but not in skeletal muscle or lungs. Similarly, cardiac O-GlcNAc levels were significantly (p< 0.05) reduced. NTg and Tg mice underwent ligation (HF) or sham and followed for four weeks using echocardiography. Although OGT deletion caused no functional change in either sham group, OGT deletion in HF significantly (p< 0.05) exacerbated cardiac dysfunction compared to NTg (Panel D). Most importantly, OGT deletion exacerbated HF mortality (Panel E).
Conclusions: We conclude that OGT is indispensable during infarct-induced HF and submit that augmented O-GlcNAc signaling represents a pro-adaptive consequence of the metabolic switch in the failing heart.
This research has received full or partial funding support from the American Heart Association, AHA National Center.