Myeloperoxidase upregulates endothelin receptor type B expression

Area of Science:

• Vascular Biology
• Inflammation Research
• Enzymology

Background:

• Neutrophil activation releases myeloperoxidase (MPO), an enzyme involved in inflammation.
• MPO's role in reducing nitric oxide (NO) bioavailability is established, but its direct effects on vascular cells are less understood.
• Understanding MPO's interaction with endothelial and smooth muscle cells is crucial for comprehending vascular tone regulation.

Purpose of the Study:

• To investigate the functional consequences of MPO binding to endothelial and smooth muscle cells.
• To determine MPO's effect on endothelin receptor type B (ETRB) expression and vascular responsiveness.
• To elucidate the signaling pathways involved in MPO-mediated changes in vascular cells.

Main Methods:

• Exposure of cultured human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HAoSMCs) to MPO.
• Gene expression analysis using real-time PCR and Western blotting to assess ETRB and ETRA levels.
• Immunofluorescence staining to confirm protein localization.
• MAP kinase pathway inhibition studies (PD98059, SB203580).
• Ex vivo organ bath studies with MPO-incubated rat femoral artery sections.

Main Results:

• MPO significantly increased ETRB gene and protein expression in HUVECs and HAoSMCs.
• MPO's enzymatic activity was necessary for the upregulation of ETRB.
• MPO-induced ETRB expression in endothelial cells was mediated by MAP kinase pathways.
• MPO selectively increased ETRB expression in smooth muscle cells, leaving ETRA unchanged.
• Ex vivo studies showed increased ETRB agonist-dependent constriction in MPO-treated rat arteries.

Conclusions:

• MPO binding to endothelial and smooth muscle cells upregulates ETRB expression through MAP kinase signaling.
• MPO influences vascular tone not only by affecting NO bioavailability but also by increasing sensitivity to vasoconstrictors.
• These findings position MPO as a key regulator of vascular tone, originating from leukocytes.