This study demonstrates how endothelial cell-specific Bag3 deletion alters the proteome in various tissues, suggesting distinct biological roles for Bag3 in endothelial function.
BAG3 (Bcl-2 associated athanogene 3) is a multifunctional protein with diverse cellular roles, but its function in endothelial cells (ECs) remains unclear. This study aimed to characterize tissue-specific changes in the EC proteome following EC-specific deletion of Bag3. We hypothesized that BAG3 loss would uniquely impact the EC proteome in each tissue. Cdh5(PAC)-CreERT2;Bag3 f/f mice were treated with tamoxifen (KO; n=18) or vehicle (WT; n=18), and ECs from brain, heart, lung, and skeletal muscle (skm) were isolated via FACS for label-free LC-MS/MS proteomics. Baseline comparisons of WT ECs revealed distinct proteomic profiles across tissues (p<0.05), including significant differences in mitochondrial protein abundance, with heart ECs enriched in complexes I, III, IV, and V. BAG3 deletion had the greatest effect in skm ECs, increasing 30 proteins (e.g., Mybpc2, L2FC=4.81; PFKM, L2FC=3.02) and decreasing 65 (e.g., CDC42, L2FC=-2.44; Prpf8, L2FC=-2.24). Overall, our data show that the EC proteome varies substantially across tissues and that BAG3 loss differentially affects a limited subset of EC proteins, particularly in skeletal muscle. These findings suggest tissue-specific roles for BAG3 in EC biology and provide new insights into its contribution to endothelial proteomic regulation.
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Terwilliger et al. (2025) studied this question.
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