Abstract
Myocardial infarction is a leading cause of death worldwide. The most effective approach to mitigate cardiac damage is timely and efficient restoration of occlusion in coronary artery. This process, ischemia/reperfusion (I/R), triggers additional damage (I/R damage), which may substantially contribute to the final cardiac infarction. Despite extensive efforts and paramount clinical interests, effective therapeutics remains vacant. A better understanding of the pathology of I/R damage is therefore urgently required. Most processes in I/R are potent inducers of the unfolded protein response (UPR), a cellular adaptive process to accommodate protein-folding stress. We have shown that the most conserved branch of the UPR, the Xbp1s pathway, is strongly induced by I/R. Using both gain- and loss-of-function approaches, we revealed that Xbp1s is necessary and sufficient to protect heart against I/R injury. We went further to discover that Xbp1s is a direct upstream transcriptional factor for multiple, key enzymes of the hexosamine biosynthetic pathway (HBP). The final production of HBP, UDP-GlcNAc, is the obligate substrate for O-GlcNAc protein modification, a prominent post-translational modification. Acute induction of O-GlcNAc modification confers strong protection against various stresses. Upregulation of Xbp1s therefore induces the HBP, UDP-GlcNAc production, consequent O-GlcNAc protein modification, and more importantly, cardioprotection against I/R damage. We found that modulation of the necroptosis pathway participates in Xbp1s-mediated cardioprotection. Elucidation of the pathology of I/R injury will greatly advance our understanding of underlying mechanisms and help identify potential therapeutic targets to tackle the devastating coronary heart disease.
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