AUTHOR=Zhong Xiaodan , Wang Tao , Xie Yang , Wang Mengwen , Zhang Wenjun , Dai Lei , Lai Jinsheng , Nie Xiang , He Xingwei , Madhusudhan Thati , Zeng Hesong , Wang Hongjie 

TITLE=Activated Protein C Ameliorates Diabetic Cardiomyopathy via Modulating OTUB1/YB-1/MEF2B Axis

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.758158

DOI=10.3389/fcvm.2021.758158

ISSN=2297-055X

ABSTRACT=<p><bold>Aims:</bold> The pathogenesis of diabetic cardiomyopathy (DCM) is complex and the detailed mechanism remains unclear. Coagulation protease activated Protein C (aPC) has been reported to have a protective effect in diabetic microvascular disease. Here, we investigated whether aPC could play a protective role in the occurrence and development of major diabetic complication DCM, and its underlying molecular mechanism.</p><p><bold>Methods and Results:</bold> In a mouse model of streptozotocin (STZ) induced DCM, endogenous aPC levels were reduced. Restoring aPC levels by exogenous administration of zymogen protein C (PC) improved cardiac function of diabetic mice measured by echocardiography and invasive hemodynamics. The cytoprotective effect of aPC in DCM is mediated by transcription factor Y-box binding protein-1 (YB-1). Mechanistically, MEF2B lies downstream of YB-1 and YB-1/MEF2B interaction restrains deleterious MEF2B promoter activity in DCM. The regulation of YB-1 on MEF2B transcription was analyzed by dual-luciferase and chromatin immunoprecipitation assays. In diabetic mice, aPC ameliorated YB-1 degradation <italic>via</italic> reducing its K48 ubiquitination through deubiquitinating enzyme otubain-1 (OTUB1) and improving the interaction between YB-1 and OTUB1. Using specific agonists and blocking antibodies, PAR1 and EPCR were identified as crucial receptors for aPC's dependent cytoprotective signaling.</p><p><bold>Conclusion:</bold> These data identify that the cytoprotective aPC signaling <italic>via</italic> PAR1/EPCR maintains YB-1 levels by preventing the ubiquitination and subsequent proteasomal degradation of YB-1 <italic>via</italic> OTUB1. By suppressing MEF2B transcription, YB-1 can protect against DCM. Collectively, the current study uncovered the important role of OTUB1/YB-1/MEF2B axis in DCM and targeting this pathway might offer a new therapeutic strategy for DCM.</p><p><bold>Translational Perspective:</bold> DCM is emerging at epidemic rate recently and the underlying mechanism remains unclear. This study explored the protective cell signaling mechanisms of aPC in mouse models of DCM. As a former FDA approved anti-sepsis drug, aPC along with its derivatives can be applied from bench to bed and can be explored as a new strategy for personalized treatment for DCM. Mechanistically, OTUB1/YB-1/MEF2B axis plays a critical role in the occurrence and development of DCM and offers a potential avenue for therapeutic targeting of DCM.</p>