SorLA modulates atheroprotective properties of CLA by regulating monocyte migration.
OBJECTIVE
We have previously shown that CLA induces regression of pre-established atherosclerotic lesions in apoE(-/-) mice. CLA is a known ligand of peroxisome proliferator activated receptors (PPARs) and it is postulated that CLA mediates its atheroprotective effects through activation of PPARs. Earlier work in our group identified the monocyte/macrophage cell as the primary cellular target of CLA. In this study we identified novel genes regulated by CLA during the regression of atherosclerosis and characterised a role for one of these, SorLA. SorLA is a member of the vacuolar protein sorting 10 protein (Vps10p) domain receptor family, which has structural homology with the LDLR family.


RESULTS
Expression of SorLA was identified with its Vps10p family member Sort1 by transcriptomic analysis of murine aorta following CLA-induced regression of atherosclerosis. Decreased expression of both receptors was confirmed by real-time PCR in the aorta of CLA-supplemented mice. SorLA protein expression was predominantly localised to monocyte/macrophage cells in the vasculature by immunohistochemistry. CLA and the PPAR-γ agonists, troglitazone, and 15-deoxy-prostaglandin (PG) J(2), decreased protein and RNA expression of SorLA in THP-1 monocytes; while pre-treatment with a PPAR-γ antagonist established a PPAR-γ dependent role for CLA regulation of SorLA. CLA inhibits monocyte migration. Consistent with a role for SorLA in mediating this response, overexpression of SorLA increased migration of THP-1 monocytes to monocyte chemoattractant protein-1 with a coincident increase in UPAR expression.


CONCLUSIONS
CLA may mediate its atheroprotective effects in part through reduced expression of SorLA and a resulting inhibition of monocyte migration in vitro.
School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. c.mccarthy@ucd.ie
Cathal
C
McCarthy
Peadar
P
O'Gaora
William G
WG
James
Monica
M
de Gaetano
Sarah
S
McClelland
Desmond J
DJ
Fitzgerald
Orina
O
Belton
D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D002839:Chromans; D044243:Linoleic Acids, Conjugated; D026901:Membrane Transport Proteins; D047495:PPAR gamma; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; C491168:Sorl1 protein, mouse; D045162:Thiazolidinediones; C046938:9,11-linoleic acid; D000077288:Troglitazone