Lipoxygenase-derived metabolites are regulators of peroxisome proliferator-activated receptor gamma-2 expression in human vascular smooth muscle cells.

Abstract:

BACKGROUND:Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family that has been implicated in cell differentiation and proliferation, glucose metabolism, macrophage development, and inflammatory responses. PPAR-gamma can be activated by a range of synthetic substances and also by products of lipid oxidation such as oxidized low-density lipoprotein, 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE). Since 12- and 15-lipoxygenase (12- and 15-LO) are expressed in human vascular smooth muscle cells (VSMCs), we set out to investigate the possible relation between PPAR-gamma and LO system in these cells. METHODS:In vitro experiments in human VSMC using standard methods. RESULTS:The LO products, 12-HETE (10(-7) mol/l), 15-HETE (10(-7) mol/l) and 13-HODE (10(-7) mol//l) increased the expression of PPAR-gamma-2 messenger RNA (mRNA) in VSMC (by 100, 50, and 100%, respectively. Rosiglitazone (1-10 micromol/l) was found to upregulate both the mRNA expression of two LO enzymes, platelet-type 12-lipoxygenase (12-LO; +70%) and 15-lipoxygenase type 2 (15-LO; +60%), and the secretion of their eicosanoid products 12- and 15-HETE. In addition, rosiglitazone-induced a threefold increase in PPAR-gamma-2 mRNA expressions and modest 50% rise in PPAR-gamma-1 mRNA expression. The effect of rosiglitazone on PPAR-gamma-2 could be entirely blocked by the LO inhibitor baicalein and restored by the addition of exogenous 12-HETE. CONCLUSIONS:These results suggest a novel amplification cycle in which PPAR-gamma activation induces production of 12- and 15-LO-derived metabolites which in turn feed back to upregulate PPAR-gamma-2's own expression. The implications of this link in VSMC pathophysiology remain to be elucidated.

journal_name

Am J Hypertens

authors

Limor R,Sharon O,Knoll E,Many A,Weisinger G,Stern N

doi

10.1038/ajh.2007.39

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

219-23

issue

2

eissn

0895-7061

issn

1941-7225

pii

ajh200739

journal_volume

21

pub_type

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