Ferulic acid ethyl ester modulates electrical remodeling in cardiomyocytes exposed to TNF-α-stimulated adipocyte secretome via Nrf2/HO-1 pathway

Abstract

Inflammatory epicardial adipose tissue impacts cardiomyocytes, creating an arrhythmogenic substrate. This study examines the effects of tumor necrosis factor-α (TNF-α)-stimulated adipocytes on atrial cardiomyocytes and the protective role of ferulic acid ethyl ester (FAEE). TNF-α-stimulated 3T3-L1-derived adipocytes were utilized and analyzed. Conditioned media from TNF-α-stimulated and TNF-α/FAEE-cotreated adipocytes were examined. Biochemical and electrophysiological studies were performed on HL-1 myocytes exposed to these media. TNF-α stimulation increased the levels of the proinflammatory proteins monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in the adipocytes and conditioned media. The ratio of phosphorylated-NF-κB (pNF-κB) to NF-κB was higher in TNF-α-stimulated adipocytes than in the control group. While the levels of IL-6, MCP-1, and pNF-κB induced by TNF-α stimulation in the adipocytes remained unchanged with FAEE cotreatment, FAEE increased the protein levels of adiponectin in the adipocytes and the conditioned medium. FAEE also upregulated the protein levels of heme-oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-erythroid 2-related factor-2 (Nrf2). The elevated adiponectin levels observed in FAEE-cotreated adipocytes were abolished following treatment with SnPP, a HO-1 inhibitor. The elevated levels of Ca²⁺/calmodulin-dependent protein kinase II and connexin 43, and the enhanced reverse mode Na⁺-Ca²⁺ exchanger current observed in HL-1 myocytes cultured in TNF-α-conditioned medium were abolished when these cardiomyocytes were cultured in TNF-α/FAEE-conditioned medium. FAEE modulates the electrical remodeling of HL-1 cardiomyocytes induced by the secretome of TNF-α-stimulated adipocytes, possibly through Nrf2/HO-1 signaling and adiponectin expression. These findings demonstrate FAEE's cardioprotective mechanisms and therapeutic potential.

Keywords: Atrial arrhythmias; Electrical remodeling; Ferulic acid ethyl ester; Inflammatory adipocytes; Secretome.