The impact of macrophage-derived cardiac injury response gene HexB (hexosaminidase B) on cardiac remodelling

• Applicant: Professor Dr. Ingo Hilgendorf
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553090013

Beta-hexosaminidases are dimeric lysosomal enzymes involved in the degradation of glycolipids, glycoproteins, and proteoglycans. Our preliminary data show that Hexb is predominantly expressed in macrophages in the heart, and its expression surges in response to both ischeamic and non-ischeamic cardiac injuries. In this proposal, we aim to explore the role of phagocytosis and pattern-recognition receptor signalling in triggering Hexb expression upon cardiac injury in macrophages in the heart, and analyse this in relation to Hexb expression in other organs. We will investigate whether high Hexb expression is associated with specific gene expression signatures in cardiac macrophage subsets. Next, we will subject transgenic mice with Hexb-deficient cardiac macrophages to myocardial infarction, and combine cardiac function testing, glycolipidome and proteome analysis, and heterocellular gene expression profiling for in-depth spatiotemporal phenotype characterisation. Finally, we plan to examine how hexosaminidases affect cardiomyocytes and fibroblasts in co-culture experiments with knockout and knockdown macrophages. Complementarily, we will explore the translational potential of our findings using in vivo and ex vivo rescue experiments with lesion-targeted enzyme supplementation or treatment with hexosaminidase chaperones which increase HEXB enzymatic activity. We hypothesize that Hexb upregulation in cardiac macrophages that perform lysosomal endocytosis and exocytosis supports heterocellular cardiac remodelling through protective heterophagy and signal transduction.

• DFG Programme: Research Grants