Activated Protein C Ameliorates Diabetic Cardiomyopathy via Modulating OTUB1/YB-1/MEF2B Axis.
Activated Protein C Ameliorates Diabetic Cardiomyopathy via Modulating OTUB1/YB-1/MEF2B Axis.
复制标题
活化蛋白 C 通过调节 OTUB1/YB-1/MEF2B 轴改善糖尿病心肌病
DOI：
10.3389/fcvm.2021.758158
复制
发表时间：
2021
影响因子：
3.6
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhong X;Wang T;Xie Y;Wang M;Zhang W;Dai L;Lai J;Nie X;He X;Madhusudhan T;Zeng H;Wang H
目的：糖尿病心肌病（DCM）的发病机制复杂，具体机制尚不清楚。凝血蛋白酶激活蛋白C（aPC）已被报道在糖尿病微血管疾病中具有保护作用。本研究旨在探讨aPC在糖尿病主要并发症DCM的发生、发展中是否具有保护作用及其分子机制。方法和结果：在链脲佐菌素（STZ）诱导的DCM小鼠模型中，内源性aPC水平降低。通过外源性给予酶原蛋白C（PC）恢复aPC水平，改善了超声心动图和侵入性血流动力学测量的糖尿病小鼠的心脏功能。aPC在DCM中的细胞保护作用由转录因子Y-box结合蛋白-1（YB-1）介导。从机制上讲，MEF 2B位于YB-1的下游，YB-1/MEF 2B相互作用抑制了DCM中有害的MEF 2B启动子活性。通过双荧光素酶和染色质免疫沉淀分析YB-1对MEF 2B转录的调节。在糖尿病小鼠中，aPC通过去泛素化酶otubain-1（OTUB 1）降低YB-1的K48泛素化并改善YB-1和OTUB 1之间的相互作用来改善YB-1的降解。使用特异性激动剂和阻断抗体，PAR 1和EPCR被鉴定为aPC依赖性细胞保护信号传导的关键受体。结论：这些数据表明，通过PAR 1/EPCR的细胞保护性aPC信号传导通过防止YB-1的泛素化和随后的蛋白酶体降解（通过OTUB 1）来维持YB-1水平。通过抑制MEF 2B转录，YB-1可以防止DCM。总之，本研究揭示了OTUB 1/YB-1/MEF 2B轴在DCM中的重要作用，靶向该通路可能为DCM提供新的治疗策略。翻译观点：扩张型心肌病近年来呈流行趋势，其发病机制尚不清楚。本研究探讨了aPC在DCM小鼠模型中的保护性细胞信号传导机制。作为前FDA批准的抗脓毒症药物，aPC沿着其衍生物可以从实验室应用到床上，并且可以探索作为DCM个体化治疗的新策略。OTUB 1/YB-1/MEF 2B轴在DCM的发生、发展中起着重要作用，为DCM的靶向治疗提供了可能。在慢性糖尿病小鼠模型中，持续高血糖损害凝血酶-血栓调节蛋白-EPCR依赖性PC激活。通过PAR 1/EPCR减少的aPC依赖性细胞保护信号抑制OTUB 1表达，导致转录因子YB-1的K48泛素化和蛋白酶体降解增强。在细胞核内，YB-1与MEF 2B启动子结合并抑制其转录。因此，YB-1的泛素化和降低的蛋白水平损害了其对MEF 2B启动子的抑制作用和增强的MEF 2B mRNA转录。随后，升高的MEF 2B表达破坏了心肌细胞的稳态，使其对DCM敏感。外源性给予PC可恢复OTUB 1/YB-1/MEF 2B依赖的细胞保护反应并改善DCM的发展。
Aims: 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. Methods and Results: 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 via 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. Conclusion: These data identify that the cytoprotective aPC signaling via PAR1/EPCR maintains YB-1 levels by preventing the ubiquitination and subsequent proteasomal degradation of YB-1 via 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. Translational Perspective: 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. 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.
登录
查看更多内容
影响因子：
50.3
作者：
Brescia P;Schneider C;Holmes AB;Shen Q;Hussein S;Pasqualucci L;Basso K;Dalla-Favera R
通讯作者：
Dalla-Favera R
影响因子：
13.6
作者：
Madhusudhan, Thati;Ghosh, Sanchita;Isermann, Berend
通讯作者：
Isermann, Berend
影响因子：
20.3
作者：
Madhusudhan T;Wang H;Ghosh S;Dong W;Kumar V;Al-Dabet MM;Manoharan J;Nazir S;Elwakiel A;Bock F;Kohli S;Marquardt A;Sögüt I;Shahzad K;Müller AJ;Esmon CT;Nawroth PP;Reiser J;Chavakis T;Ruf W;Isermann B
通讯作者：
Isermann B
影响因子：
7.3
作者：
Kilkenny, Carol;Browne, William;Altman, Douglas G.
通讯作者：
Altman, Douglas G.
影响因子：
10.8
作者：
Damanafshan, Amin;Elzenaar, Ies;van Oort, Ralph J.
通讯作者：
van Oort, Ralph J.