Key result
Pharmacological inhibition of CK2 with TBB significantly abrogated cardiac fibroblast activation and oxidative stress induced by the secretome of TGFβ-stimulated cardiomyocytes.
Why the study?
Although the secretome of dysfunctional cardiomyocytes is an important driver of pathological fibroblast reprogramming in cardiac fibrosis, understanding of downstream molecular players remains limited.
Inhibition of casein kinase 2 (CK2) abrogates cardiac fibroblast activation and oxidative stress driven by the secretome of dysfunctional cardiomyocytes, offering a potential target against cardiac fibrosis.
Hypothesis-generating for cardiomyocyte-fibroblast crosstalk in fibrosis; in vivo studies needed before translational relevance.
Pathological reprogramming of cardiomyocyte and fibroblast proteome landscapes drive the initiation and progression of cardiac fibrosis. Although the secretome of dysfunctional cardiomyocytes is emerging as an important driver of pathological fibroblast reprogramming, our understanding of the downstream molecular players remains limited. Here, we show that cardiac fibroblast activation (αSMA + ) and oxidative stress mediated by the secretome of TGFβ‐stimulated cardiomyocytes is associated with a profound reprogramming of their proteome and phosphoproteome landscape. Within the fibroblast global proteome there was a striking dysregulation of proteins implicated in extracellular matrix, protein localisation/metabolism, KEAP1‐NFE2L2 pathway, lysosomes, carbohydrate metabolism, and transcriptional regulation. Kinase substrate enrichment analysis of phosphopeptides revealed potential role of kinases (CK2, CDK2, PKC, GSK3B) during this remodelling. We verified upregulated activity of casein kinase 2 (CK2) in secretome‐treated fibroblasts, and pharmacological CK2 inhibitor TBB (4,5,6,7‐Tetrabromobenzotriazole) significantly abrogated fibroblast activation and oxidative stress. Our data provides molecular insights into cardiomyocyte to cardiac fibroblast crosstalk, and the potential role of CK2 in regulating cardiac fibroblast activation and oxidative stress.
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Claridge et al. (2023) studied Cardiac fibrosis. CK2 inhibitor TBB was evaluated on Fibroblast activation and oxidative stress. Pharmacological inhibition of CK2 with TBB significantly abrogated cardiac fibroblast activation and oxidative stress induced by the secretome of TGFβ-stimulated cardiomyocytes.
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