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bioRxiv · 10.1101/2024.12.04.626922

The Cardioprotective Effect of Ischemic Postconditioning is Mediated by Inhibiting RAP2C-MAP4K4 Pathway

Zhang, M.·Yan, P.·Yu, Z.·Hu, Z.·Li, S.·Juaiti, M.
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Abstract

BackgroundIschemic postconditioning (PostC) serves as a vital defense for cardiomyocytes against the deleterious effects of ischemia/reperfusion (I/R) injury, the beneficial effects could be further enhanced through pharmacological strategies. Our prior research demonstrated upregulated expression of the GTP-binding protein RAP2C in H9C2 cells post hypoxia-reoxygenation (H/R). The cardioprotective effects of RAP2C and underlying mechanisms are unclear. We therefore explored the role of RAP2C in PostC-induced cardioprotection against I/R injury. MethodsOpen-chest rat I/R and primary cultured cardiomyocytes H/R models were used. RAP2C and MAP4K4 expression was detected by immunohistochemistry and Western blotting. The BioGRID and STRING databases were tapped to predict the RAP2C-MAP4K4 binding, which was confirmed by co-immunoprecipitation and immunofluorescence. ResultsResults indicated that I/R and H/R upregulated the protein levels of RAP2C, MAP4K4, phospho-JNK, phospho-P38, and phospho-ERK, concomitant with increased apoptosis. PostC mitigated these effects. The pro-apoptotic impacts and the activation of the MAPK pathway induced by H/R were attenuated by RAP2C knockdown and intensified by RAP2C overexpression. H/R increased the interaction between RAP2C and MAP4K4, and PostC attenuated this effect. MAP4K4 knockdown reduced the pro-apoptotic and MAPK-activating effects induced by both RAP2C overexpression and hypoxia/reoxygenation (H/R). ConclusionsThese results demonstrate that PostC reduces cardiomyocyte apoptosis via modulating RAP2C/MAP4K4 pathways, suggesting their potential as therapeutic targets for the treatment of ischemic heart disease.

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Zhang, M., Yan, P., Yu, Z., Hu, Z., Li, S., Juaiti, M.. 2024-12-05. The Cardioprotective Effect of Ischemic Postconditioning is Mediated by Inhibiting RAP2C-MAP4K4 Pathway. https://doi.org/10.1101/2024.12.04.626922

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