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  • With the aim to identify potential novel targets in CVD

    2022-05-09

    With the aim to identify potential novel targets in CVD, we applied proteome analyses on vascular tissue of these frequently used mouse models of atherosclerotic disease in the presence and/or absence of diabetes. Potential targets for intervention identified with this approach were validated in human vascular tissue of patients with CVD and their impact was further assessed in vitro. Our results reveal dysregulation of histone modifiers in CVD and suggest an involvement of the KDM5 histone demethylases in vessel formation, being of potential therapeutic interest.
    Materials and methods
    Results
    Discussion With this work, we aimed to characterize protein changes associated with CVD using high resolution proteome analysis. These changes may have a potential to serve as biomarkers for disease, or even as possible therapeutic targets. We used three widely employed disease models representing different disease aetiologies (Ldlr−/−, Ldlr−/−STZ, ApoE−/−STZ) thus allowing for the definition of as possible, ‘common’ atherosclerosis-associated proteomic alterations [13]. Of note, a good overlap was also observed when comparing the common proteins of the aforementioned three animal models with changes observed in ApoE−/− versus WT mice (111 common proteins with the same xpo 1 trend at statistical significant levels – Supplementary Table 8). Male mice were selected for this study since they develop more pronounced atherosclerosis than the females [35]. It should be noted that protein changes unique per model are also observed (as may be seen in Fig. 2a and Supplementary Tables 2 and 3) which even though not investigated in this study, may merit further investigation. To the best of our knowledge this is the first study that describes common proteomic alterations in these three atherosclerotic mouse models. An in-depth analysis of these protein changes suggests that they reflect different well-characterized atherosclerosis-associated mechanisms such as inflammation [19], metabolism [20], oxidative stress [21], and extracellular matrix remodeling [23]. Further comparison of the proteomics findings from the animal models with their orthologues from the proteomic profiling of human vascular tissues from patients affected by CVD, revealed a high degree of overlap at the pathway level, although a small overlap at the individual molecule level. This has been also observed in studies comparing the overlap of human genes in coronary artery disease (CAD) identified by genome-wide association studies (GWAS) with those from atherosclerotic mouse models [36]. In these studies, although an overlap of only 18.4% of human CAD genes with mouse orthologs was detected, their relevance at pathways was significantly higher (over than 50% being consistent between the two species) [36]. In our case, the observed relatively small overlap at the individual molecule level may be additionally attributed to the use of different vessel types (central in mice versus peripheral and central in humans). Nevertheless and despite this variability, six common proteins were identified. A more detailed investigation of the expression of these proteins in a gender-specific manner is required to exclude with high confidence an impact of gender on our findings. Of note, among them was cathepsin D (CTSD) whose increased expression levels have been previously associated with atherosclerosis [37] and the ketogenic enzyme hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2) whose upregulation may be implicated in type 1 diabetes induced cardiac dysfunction [38]. Furthermore, proteins with a possible role in CVD were also included such as the immunoglobulin heavy chain mu (IGHM) which was significantly increased in B cells in the artery tertiary lymphoid organs (ATLOs) with the latter associated with B cell responses in the atherosclerotic aortas [39] and titin (TTN), a highly abundant protein in striated muscle whose truncated variants have been associated with several cardiomyopathies [40]. Proteins without a known/previous implication in CVD such as the zinc finger FYVE domain-containing protein 1 (ZFYVE1) which is a protein participating to autophagosome formation [41], and KDM5D were also included with the latter being highlighted as a predominant CVD-associated change in both species. KDM5D was also found upregulated (fold change = 50.8 in cases versus controls) yet did not reach statistical significance in the ApoE−/− mice (in the absence of diabetes) when comparing with WT mice (data not shown).