The G-protein coupled receptor ChemR23 determines smooth muscle cell phenotypic switching to enhance high phosphate-induced vascular calcification.

Abstract

AIMS:

Vascular calcification, a marker of increased cardiovascular risk, is an active process orchestrated by smooth muscle cells. Observational studies indicate that omega-3 fatty acids protect against vascular calcification, but the mechanisms are unknown. The G-protein coupled receptor ChemR23 transduces the resolution of inflammation induced by the omega-3-derived lipid mediator resolvin E1. ChemR23 also contributes to osteoblastic differentiation of stem cells and bone formation, but its role in vascular calcification is unknown. The aim of this study was to establish the role of ChemR23 in smooth muscle cell fate and calcification.

METHODS AND RESULTS:

Gene expression analysis in epigastric arteries derived from patients with chronic kidney disease and vascular calcification revealed that ChemR23 mRNA levels predicted a synthetic smooth muscle cell phenotype. Genetic deletion of ChemR23 in mice prevented smooth muscle cell de-differentiation. ChemR23-deficient smooth muscle cells maintained a non-synthetic phenotype and exhibited resistance to phosphate-induced calcification. Moreover, ChemR23-deficient mice were protected against vitamin D3-induced vascular calcification. Resolvin E1 inhibited smooth muscle cell calcification through ChemR23. Introduction of the Caenorhabditis elegans Fat1 transgene, leading to an endogenous omega-3 fatty acid synthesis and hence increased substrate for resolvin E1 formation, significantly diminished the differences in phosphate-induced calcification between ChemR23+/+ and ChemR23-/- mice.

CONCLUSION:

This study identifies ChemR23 as a previously unrecognized determinant of synthetic and osteoblastic smooth muscle cell phenotype, favouring phosphate-induced vascular calcification. This effect may be of particular importance in the absence of ChemR23 ligands, such as resolvin E1, which acts as a calcification inhibitor under hyperphosphatic conditions.

• Authors: Miguel Carracedo, Gonzalo Artiach, Anna Witasp, Joan Clària, Mattias Carlström, Andres Laguna-Fernandez, Peter Stenvinkel, Magnus Bäck
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 115 Issue 10 Pg. 1557-1566 (08 01 2019) ISSN: 1755-3245 [Electronic] England
• PMID: 30597013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected].

Chemical References

• CMKLR1 protein, human
• CMKLR1 protein, mouse
• Cadherins
• Phosphates
• Receptors, Chemokine
• fat1 protein, mouse
• Cholecalciferol
• Eicosapentaenoic Acid
• 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid

Topics

• Adaptation, Physiological (drug effects)
• Adult
• Aged
• Animals
• Cadherins (genetics, metabolism)
• Cholecalciferol
• Disease Models, Animal
• Eicosapentaenoic Acid (analogs & derivatives, pharmacology)
• Female
• HEK293 Cells
• Humans
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Osteogenesis (drug effects)
• Phosphates (metabolism)
• Rats
• Receptors, Chemokine (deficiency, drug effects, genetics, metabolism)
• Signal Transduction
• Vascular Calcification (chemically induced, metabolism, pathology, prevention & control)