Reduced circulating 20-hydroxyeicosatetraenoic acid and ACE2 in acute coronary syndrome with exploratory cell-based...

Progression of ischemic heart disease to acute coronary syndrome (ACS) is fueled by endothelial dysfunction and disruptions in vascular signaling pathways. The relationship between the angiotensin-converting enzyme 2 (ACE2)/renin-angiotensin system (RAS) axis and eicosanoid metabolism is still not fully understood. This study aimed to investigate whether changes in circulating ACE2 and 20-hydroxyeicosatetraenoic acid (20-HETE) reflect dysregulation of a combined ACE2/RAS-eicosanoid axis in ACS and to evaluate the diagnostic and functional significance of 20-HETE. We studied 122 patients with ischemic heart disease (including stable coronary artery disease (SCAD) and ACS) and 54 controls. Levels of circulating ACE2 and 20-HETE were measured using ELISA. Additionally, in vitro experiments with cell culture models were conducted to evaluate how pharmacological modulation of the ACE2/RAS axis affects nitric oxide (NO) production, inflammatory signaling, and CYP4F2 expression. Both ACE2 and 20-HETE levels were significantly lower in ACS compared to SCAD and controls (p < 0.001). Circulating 20-HETE effectively distinguished ACS from SCAD with an AUC of 0.91. In endothelial cells, altering the ACE2/RAS axis impacted NO availability and inflammatory gene expression, correlating with changes in CYP4F2 levels. 20-HETE affected cellular metabolic activity and GPR75 signaling, indicating a functional connection between RAS signaling and eicosanoid pathways. Lower circulating 20-HETE levels are associated with disruption of the integrated ACE2/RAS-eicosanoid axis, which is linked to endothelial dysfunction in ACS. These results suggest that 20-HETE may serve not only as a biomarker but also as part of a broader vascular signaling network related to acute coronary instability.