Targeting Cardiomyocyte Proliferation via Modification of the S1P Signaling and the Hippo Signaling Pathway



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Heart-related diseases are on the top list of the leading cause of death worldwide due to the heart cannot heal itself. Current methods for curing the damaged heart are not sufficient and several new methods are still under research. Unfortunately, the organ transplant option is not enough due to the demanding number of patients. For those reasons, we have targeted heart cells, especially cardiomyocytes to induce cell division and thus heal the damaged tissue by replacing it. The Hippo pathway is known to control organ size and cell division, and S1P signaling is another mechanism for inducing cell division. Inactivation of the Hippo signaling pathway leads its effector protein YAP to translocate into the nucleus and induce cell division genes. NF2, a Hippo pathway upstream component, is targeted by phosphatidic acid to inactivate the Hippo pathway. Also, small molecule screening was performed by virtual docking and nine candidates were found to target the NF2 binding pocket. S1P lipid signaling molecules affect several signaling pathways and one of them is the Hippo pathway. Cardiomyocytes were initiating the cell cycle upon the addition of S1P. In addition, RNA sequencing data has shown this molecule is affecting important signaling pathways such as Notch, Wnt, BMP, mTOR, angiogenesis, and telomere maintenance. Interestingly, telomere elongation was induced with S1P in cardiomyocytes for at least five days together with increasing telomere maintenance factors. Having constitutively active Sphingosine kinase would produce S1P within the cells and could be used as therapeutics. Mutation on phosphorylation amino acid Serine 225 was performed and shown to be more active compared to wild type. These results are promising to heal the damaged heart.



S1P, SphK1, PA, Drug discovery, Cardiomyocyte, Heart