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Targeting the miR-493-5p/OTUB1 Axis to Mitigate Mitochondrial Dysfunction in Diabetic Cardiomyopathy.

Xiaodan Zhong,Yu Li,Yang Xie,Yueqi Zhang,Mengwen Wang,Hongcheng Jiang,Zixuan Liu,Lei Dai,Lina Li,Honghui Wang,T. Madhusudhan,Hesong Zeng,Hongjie Wang

Published 2025 in European Journal of Pharmacology

ABSTRACT

AIMS Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and frequently progresses to heart failure. Although the deubiquitinase OTUB1 has demonstrated protective effects in DCM, the upstream regulatory mechanisms governing its expression and their influence on mitochondrial function remain unclear. METHODS We used a short-term insulinopenic diabetic mouse model supplemented with exogenous protein C (PC) to investigate the role of activated protein C (aPC) in regulating OTUB1 during early-stage DCM. A thrombomodulin-mutant (TMPro/Pro) mouse model, which limits endogenous PC activation, was employed to assess long-term effects. Additionally, a microRNA miR-493-5p sponge was delivered via recombinant adeno-associated virus (rAAV) to evaluate the therapeutic potential of miR-493-5p inhibition. RESULTS Exogenous PC supplementation preserved cardiac function and restored OTUB1 protein levels in early-stage DCM without affecting Otub1 mRNA expression. In contrast, TMPro/Pro mice exhibited exacerbated cardiac dysfunction and reduced OTUB1 protein abundance. Mechanistically, we identified miR-493-5p as a direct translational repressor of OTUB1, which was upregulated in diabetic hearts and downregulated by aPC through endothelial protein C receptor-protease-activated receptor 1 signaling. Both in vitro and in vivo experiments confirmed that miR-493-5p impairs OTUB1-mediated mitochondrial function, resulting in cardiomyocyte apoptosis. Inhibition of miR-493-5p via rAAV-sponge delivery restored OTUB1 levels, improved mitochondrial morphology, and significantly enhanced cardiac function in diabetic mice. CONCLUSION Our findings identify the aPC/miR-493-5p/OTUB1 axis as a critical regulatory pathway in DCM pathogenesis. Targeting this axis may represent a promising therapeutic strategy for preserving mitochondrial integrity and preventing diabetic cardiac dysfunction.

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