Animal study reveals that activated protein C protects against diabetic cardiomyopathy in diabetic mice, indicating a therapeutic role for the OTUB1-YB-1-MEF2B pathway.
Graphical Abstract In mouse model of chronic diabetes mellitus, persistent hyperglycemia impaired thrombin-thrombomodulin-EPCR dependent PC activation. The reduced aPC-dependent cytoprotective signaling via PAR1/EPCR supressed OTUB1 expression resulting in augmented K48 ubiquitination and proteasomal degradation of the transcription factor YB-1. Within the nucleus, YB-1 binds to MEF2B promoter and restrains its transcription. Accordingly, ubiquitination and reduced protein levels of YB-1 compromised its inhibitory effect on MEF2B promoter and enhanced MEF2B mRNA transcription. Subsequently, elevated MEF2B expression disrupted the homeostasis of cardiomyocytes, rendering them susceptible to DCM. Exogenous administration of PC restores OTUB1/YB-1/MEF2B dependent cytoprotective responses and ameliorates development of DCM.
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Zhong et al. (2021) studied this question.
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