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  • KDM D also known as JARID D or SMCY is


    KDM5D (also known as JARID1D or SMCY) is encoded on the Y chromosome and until now it has been implicated in prostate cancer invasion and metastasis [42], spermatogenesis [43], and sex-specific tissue transplantation rejection [44]. KDM5D acts as a direct epigenetic modulator, and as one of the four members of the KDM5 family of histone demethylases, specifically demethylates trimethylated and dimethylated Lys-4 of histone H3 [29]. The elevated expression of KDM5D in the human tissues of patients with CVD was accompanied by a reduction of its substrate (H3K4me3) implying increased activity of KDM5D. Alteration in the trimethylated state of H3K4 has been previously related to the development of heart failure in humans and rat models [45] and also associated with the physiological function of cardiomyocytes [46]. Mutations in genes involved in the H3K4me pathway (production, removal or reading of H3K4me), including KDM5A and KDM5B, have been implicated in the pathogenesis of congenital heart disease (CHD) [47]. Given this published evidence with respect to H3K4 and the observed increased KDM5D and concomitant decreased H3K4me3 levels in human tissues of patients with CVD, we investigated the impact of the KDM5-C70 inhibitor on HUVEC. This compound targets all four members of the KDM5 family, is a cell-permeable prodrug with no reported cytotoxicity, and shows selectivity for KDM5 family members compared to KDM6 and KDM4 [32,33]. Considering that endothelial cell dysfunction is an important contributor in atherosclerosis [1] we employed HUVEC. Inhibition of KDM5 activity increased the H3K4me3 levels and significantly attenuated the proliferation rate, the migratory capacity and the tube-forming ability of the endothelial pka inhibitor in vitro. These findings are in line with another study that describes impaired angiogenic properties of the endothelial cells after inhibition of KDM5B and gene silencing with shRNA, linked to induced expression of the antiangiogenic transcription factor HOXA5 [48]. Interpretation of our findings in the context of atherosclerosis suggests that treatment with a KDM5 inhibitor may be beneficial, considering that the atherosclerotic plaques are characterized by increased neovascularization that contributes to intraplaque hemorrhage and plaque progression [49]. In response to hypoxia and to the VEGF gradient in the atherosclerotic lesion, the endothelial cells of the vasa vasorum switch from a quiescent phenotype to a highly proliferative and migratory state to start sprouting and forming the new vessels [49]. Since KDM5 inhibition significantly attenuated growth and function of endothelial cells in vitro, it may have therapeutic potential in vivo- a working hypothesis warranting further investigation. Collectively, in this study, by applying a systematic approach that included high-throughput proteomics of mouse models and human vascular tissues as well as in vitro assays, a role for KDM5 histone demethylases in CVD, likely via affecting H3K4 methylation, is suggested. The key findings of this study are summarized in Fig. 6. In addition to multiple high confidence proteomic changes reflecting common molecular manifestations of atherosclerosis, further underlining the validity of the approach, other yet unknown proteomic changes were identified, which may be of significant value in further systems biology approaches and model selection for pre-clinical studies.
    Limitations of the study Our proteomics based approach using mouse and human vascular tissues with CVD indicates KDM5D as a novel candidate pharmacological target associated with CVD progression. However, there are several shortcomings of this study with regards to the role of KDM5D in the context of CVD. Given the fact that the cellular composition of the aortas especially in the areas of the lesions is quite heterogeneous, further experiments and efforts to identify which cells contribute to the elevated expression of KDM5D appear well justified. Along the same lines, in this study we focused on the impact of KDM5 inhibition on endothelial cells, given that endothelial dysfunction is a crucial event in atherosclerosis and impact of H3K4 methylation on endothelial migration and proliferation has been reported. Nevertheless, studying the impact of KDM5 inhibition on other cell types involved in atherosclerotic plaque formation including smooth muscle cells and inflammatory cells is well justified, especially given the reported impact of H3K4 methylation on inflammation [50]. Additionally, characterization of the genes affected upon the KDM5D-mediated alteration of the methylation status of H3K4 may be valuable to improve our understanding of the mechanism of KDM5 inhibition. In parallel, the impact of inhibition of KDM5 in vivo on CVD preferably in a gender-specific manner is needed. However this is currently limited due to the lack of well characterized inhibitors applicable for in vivo studies. Although limitations of the current study, these are multiple research avenues to be further explored, for which the presented study pka inhibitor forms a solid starting point.