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

  • Sci Rep. 2026 Jun 10. doi: 10.1038/s41598-026-56316-9.
Ieva Čiapienė  1 ,  Aistė Ivanauskienė  2 ,  Nora Kupstytė-Krištaponė  1  2 ,  Vaiva Lesauskaitė  1 ,  Robertas Pranevičius  1  2 ,  Gintarė Šakalytė  1  2 ,  Daiva Stanislovaitienė  3 ,  Cynthia Sithole  1  4 ,  Vacis Tatarūnas  5
Affiliations
  • 1. Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, Kaunas, LT, 50162, Lithuania.
  • 2. Heart Center, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, LT, 50161, Lithuania.
  • 3. Department of Ophthalmology, Lithuanian University of Health Sciences, Eiveniu 2, Kaunas, LT, 50161, Lithuania.
  • 4. Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina, 0031, Pretoria, South Africa.
  • 5. Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, Kaunas, LT, 50162, Lithuania. [email protected].
PMID: 42270785 DOI: 10.1038/s41598-026-56316-9
Abstract

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.

Keywords
20-HETE; ACE2; acute coronary syndrome; ischemic heart disease; renin-angiotensin system; stable coronary artery disease.
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