20-Hydroxyeicosatetraenoic acid (20-HETE): Bioactions, receptors, vascular function, cardiometabolic disease and beyond

Abstract

Vascular function is dynamically regulated and dependent on a bevy of cell types and factors that work in concert across the vasculature. The vasoactive eicosanoid, 20-Hydroxyeicosatetraenoic acid (20-HETE) is a key player in this system influencing the sensitivity of the vasculature to constrictor stimuli, regulating endothelial function, and influencing the renin angiotensin system (RAS), as well as being a driver of vascular remodeling independent of blood pressure elevations. Several of these bioactions are accomplished through the ligand-receptor pairing between 20-HETE and its high-affinity receptor, GPR75. This 20-HETE axis is at the root of various vascular pathologies and processes including ischemia induced angiogenesis, arteriogenesis, septic shock, hypertension, atherosclerosis, myocardial infarction and cardiometabolic diseases including diabetes and insulin resistance. Pharmacologically, several preclinical tools have been developed to disrupt the 20-HETE axis including 20-HETE synthesis inhibitors (DDMS and HET0016), synthetic 20-HETE agonist analogues (20-5,14-HEDE and 20-5,14-HEDGE) and 20-HETE receptor blockers (AAA and 20-SOLA). Systemic or cell-specific therapeutic targeting of the 20-HETE-GPR75 axis continues to be an invaluable approach as studies examine the molecular underpinnings activated by 20-HETE under various physiological settings. In particular, the development and characterization of 20-HETE receptor blockers look to be a promising new class of compounds that can provide a considerable benefit to patients suffering from these cardiovascular pathologies.

Keywords: 20-HETE; GPR40; GPR75; Obesity; Vascular function.

Fig. 1

20-HETE receptor signaling. (A) Molecular mechanisms and pathways associated with the pairing of 20-HETE and GPR75 across (1) endothelial cells, (2) vascular smooth muscle cells and (3) adipose tissues. (B) The signaling pathways associated with the pairing of 20-HETE and the free fatty acid receptor (FFAR/GPR40). Glucose drives changes in intracellular calcium that alongside 20-HETE, promotes and enhance increases in glucose-stimulated insulin secretion through the activation of FFAR1/GPR40 in beta cells of the pancreas.

Fig. 2

20-HETE regulates the neovascularization of ischemic tissue. Schematic illustrating the role of 20-HETE as a regulator of angiogenesis and neovascularization during ischemic injury. 20-HETE promotes the mobilization of endothelial progenitor cells (EPCs) from the bone marrow to the circulation and target site of angiogenesis.

Fig. 3

20-HETE increases myocardial ischemia and it impairs coronary collateral growth in the heart. Illustration highlighting the role of 20-HETE in the rat model of metabolic syndrome (JCR) as a driver of inflammation, endothelial dysfunction, apoptosis and neutrophil infiltration blocking the generation of coronary collateral growth across collateral-dependent zones (CZ) compared to normal zones (NZ). The pharmacological antagonism of 20-HETE via 20-SOLA restores the generation of coronary collateral growth and alleviates the heart from the pro-inflammatory bioactions associated with 20-HETE.

Fig. 4

The 20-HETE-GPR75 axis. Systemic elevations in 20-HETE and the activation of its receptor, GPR75, drive various vascular pathologies, i.e., hypertension, vascular remodeling, myocardial infarction/heart failure, atherosclerosis and cardiometabolic disease. The 20-HETE-GPR75 axis can be augmented by the use of 20-HETE synthesis inhibitors (DDMS, HET0016), 20-HETE agonist analogues (20-5,14-HEDE, 20-5,14-HEDGE) or GPR75 receptor blockers (AAA, 20-SOLA (SOLA)).