Hexosamine signaling reduces ER stress‐induced cardiomyocyte death

We have demonstrated that the post‐translational modification of O‐linked beta‐N‐acetylglucosamine (O‐GlcNAc) confers cardioprotection at least partially through mitochondrial dependent mechanisms. Because ischemia/hypoxia causes endoplasmic reticulum (ER) stress, we evaluated a potential link between O‐GlcNAc signaling and ER stress. We pharmacologically induced ER stress to define a potential link between these two processes. Normoxic induction of ER stress (tunicamycin or brefeldin A) augmented O‐GlcNAc signaling in cardiomyocytes (p<0.05). Prior to induction of ER stress, we adenovirally overexpressed or pharmacologically inhibited O‐GlcNAcase, the enzyme responsible for O‐GlcNAc removal. AdO‐GlcNAcase reduced (p<0.05) ER stress‐mediated elevation in O‐GlcNAc levels and aggravated cell death. Conversely, pharmacological inhibition of O‐GlcNAcase resulted in further elevation in O‐GlcNAc levels and significantly (p< 0.05) attenuated ER stress‐induced cell death. We conclude that ER stress acutely recruits O‐GlcNAc signaling, and, such enhanced O‐GlcNAc signaling represents a partially pro‐adaptive response to reduce ER stress‐induced cell death. These results provide new insights into a possible interaction between O‐GlcNAc signaling and ER stress and may partially explain the mechanism of O‐GlcNAc mediated cardioprotection. Funding: NIH, AHA, and VA