Treatment of human cardiac fibroblasts with the protein arginine deiminase inhibitor BB-Cl-amidine activates the Nrf2/HO-1 signaling pathway

• DOI: 10.1016/j.biopha.2023.115443
• Publication Date: 2023-09-11T09:10:09Z
• Authors: Aneta Stachowicz; Alia Sadiq; Brian Walker; Niveda Sundararaman; Justyna Fert-Bober
• Keywords: Citrullination; Cardiac Fibrosis; Myofibroblast

Cardiac fibrosis contributes to end-stage extracellular matrix remodeling and heart failure (HF). fibroblasts (CFs) differentiate into myofibroblasts (myoFbs) preserve the structural integrity of heart; however, molecular mechanisms regulating CF transdifferentiation remain poorly understood. Protein arginine deiminase (PAD), which converts citrulline, has been shown play a role in myocardial infarction, fibrosis, HF. This study aimed investigate PAD differentiation myoFbs identify citrullinated proteins that were associated with phenotypic changes CFs.Gene expression analysis showed PAD1 PAD2 isoforms, but not PAD4 abundant both CFs myoFbs, was significantly upregulated myoFbs. The pan-PAD inhibitor BB-Cl-amidine (BB-Cl) downregulated mRNA as well protein marker COL1A1 Interestingly, proteomic approach pointed activation Nrf2/HO-1 signaling pathway upon BB-Cl treatment administration resulted upregulation HO-1 at gene levels Importantly, citrullination landscape consisting 86 novel sites focal adhesion (FN1(R1054)), inflammation (TAGLN(R12)) DNA replication (EEF2(R767)) pathways identified.In summary, we revealed increased via Nrf2 pathway, could prevent excessive tissue damage, thereby leading substantial clinical benefits for cardiac fibrosis.