Phoenixin-20 Prevents ox-LDL-Induced Attachment of Monocytes to Human Aortic Endothelial Cells (HAECs): A Protective Implication in Atherosclerosis

Abstract

Background: The cause of atherosclerosis is not known, and therefore the current treatment options are limited. In the present study, we aimed to investigate the effects of Phoenixin 20 and its receptor G protein-coupled receptor 173 (GPR173) against ox-LDL-induced endothelial dysfunction.Materials and Methods: Human aortic endothelial cells (HAECs) were treated with 10 μg/ml ox-LDL in the presence or absence of phoenixin 20. Gene expression of GPR173, ICAM-1, VCAM-1, IL-1β, IL-8, MCP-1, and NOX-4 were measured by real time PCR. Protein expression was assayed by western blot analysis. Secretions of pro-in ammatory cytokines were measured by ELISA. The attachment of THP-1 monocytes to HAECs was detected using calcein-AM staining. Transcriptional activity of NF-κB was measured using dual-luciferase reporter assay.Results: Our ndings indicate that ox-LDL signi cantly lowered the expression of GPR173 in HAECs and triggered an increase in ROS, NOX-4, and proin ammatory cytokine expression. Importantly, we demonstrate that agonism of GPR173 using phoenixin 20 signi cantly ameliorated these harmful effects of ox-LDL. We also show that agonism of GPR173 can prevent the attachment of monocytes to endothelial cells, which is an important therapeutic approach to prevent atherogenesis. Conclusion:Here, for the rst time to our knowledge, we provide a basis for future research on the role of GPR173 as a new potential treatment against atherosclerosis.

Investigation of serum phoenixin levels in patients with hypertension

“…Endothelium plays an important role in pathogenesis of many diseases and cardiovascular problems such as atherosclerosis and HT 21 . Wei et al reported that GPR173 agonism by PNX-20 plays a protective role against ox-LDL-induced endothelial dysfunction 13 . VSMCs are major components of the vascular wall and serve to mediate hemodynamic vessel functions, playing a crucial role in regulating blood pressure in physiological conditions and HT.…”

“…PNX-14 has been reported to regulate proliferation and apoptosis of vascular smooth muscle cells (VSMCs) 12 . GPR173 agonism by PNX-20 plays a protective role against ox-LDL-induced endothelial dysfunction 13 . Based on these data, this study was designed to evaluate serum concentrations of PNX-14 and PNX-20 in HT patients and healthy controls and the clinical value of these peptides as novel biomarkers for HT.…”

Regulation and physiological functions of phoenixin

“…Phoenixin-20 inhibited LPS-induced inflammation of dental pulp cells, and phoenixin-20 inhibited the release of pro-inflammatory cytokines and inflammatory mediators induced by LPS, including monocyte chemotactic protein-1 (MCP-1), IL-6, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), MMP-2 and MMP-9 ( Sun, et al, 2020 ). Phoenixin-20, activating GPR173, significantly ameliorated oxidized low-density lipoprotein (ox-LDL) induced harmful effects by suppressing the NF-κB pathway in human aortic endothelial cells, and the harmful effects were presented as an increase in ROS, NOX-4, IL-1β, interleukin-8 (IL-8), and MCP-1 expression, as well as ICAM-1 and VCAM-1 release ( Wei et al, 2021 ). Recently, Zandeh-Rahimi et al found that phoenixin-14 could protect indomethacin-induced duodenal ulcer in rats, and phoenixin-14 exhibited a decrease in serum levels of inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-12), malondialdehyde and myeloperoxidase activity, and an increase on SOD and catalase activity in duodenal ulcer ( Zandeh-Rahimi et al, 2022 ).…”

The Regulation of Phoenixin: A Fascinating Multidimensional Peptide

“…In atherosclerosis, GPR173 expression is reduced in human aortic endothelial cells upon exposure to oxidized low-density lipoprotein, thereby implying a role for PNX in disease onset. Moreover, PNX-20 agonism can improve disease progression by preventing the attachment of THP-1 monocytes to human aortic endothelial cells and attenuating the NF-κB pathway [ 51 ].…”