Adipocyte enhancer binding protein 1 (AEBP1) as a potential therapeutic target to combat cardiac fibrosis

Fibrosis is one of the major hallmarks of heart failure (HF) progression and is characterized by fibroblast activation and excess extracellular matrix (EMC) deposition. RNA sequencing of myocardial tissue acquired from HF patients showed a significant upregulation of adipocyte enhancer binding protein (Aebp1) and increased AEBP1 protein expression was observed in regions around the infarct. AEBP1 is a secreted protein known to bind to TGFß-receptor and activate fibroblasts. AEBP1 has been identified in lung and liver fibrosis as a potential therapeutic target to combat fibrosis. However, the role of AEBP1 in cardiac fibrosis is not well understood and requires further investigation. Cultured human cardiac fibroblasts stimulated with TGFß showed a significant increase in activated fibroblast markers like α-smooth muscle actin (⍺SMA) and transgelin (SM22) indicating fibroblast activation. AEBP1 also showed a significant increase in activated fibroblasts when compared to quiescent fibroblasts. Further investigation showed that overexpressing AEBP1 in fibroblasts leads to its activation, evident from significant upregulation of fibroblast activation markers (⍺SMA & SM22) and ECM proteins like collagen (Col1A1) and osteopontin (OSPN), independent of TGFß signaling. In contrast, AEBP1 knockdown prevented active myofibroblast proliferation (evident from decrease in SM22) and a significant reduction in ECM production. In-vivo myocardial infarction (MI) mice model studies also showed a significant increase in serum AEBP1, 4-days post MI and immunohistochemistry analysis showed increased localization of AEBP1 in periinfarct regions making AEBP1 a potential target to prevent active cardiac fibrosis.