PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.
BACKGROUND
Adhesion molecule expression on the endothelial cell (EC) surface is critical for leukocyte recruitment to atherosclerotic lesions. Better understanding of transcriptional regulation of adhesion molecules in ECs may provide important insight into plaque formation. Peroxisome proliferator-activated receptor-alpha (PPARalpha), a member of the nuclear receptor family, regulates gene expression in response to certain fatty acids and fibric acid derivatives. The present study investigated PPARalpha expression in human ECs and their regulation of vascular cell adhesion molecule-1 (VCAM-1).


RESULTS
Immunohistochemistry revealed that human carotid artery ECs express PPARalpha. Pretreatment of cultured human ECs with the PPARalpha activators fenofibrate or WY14643 inhibited TNF-alpha-induced VCAM-1 in a time- and concentration-dependent manner, an effect not seen with PPARgamma activators. Both PPARalpha activators decreased cytokine-induced VCAM-1 mRNA expression without altering its mRNA half-life. Transient transfection of deletional VCAM-1 promoter constructs and electrophoretic mobility shift assays suggest that fenofibrate inhibits VCAM-1 transcription in part by inhibiting NF-kappaB. Finally, PPARalpha activators significantly reduced adhesion of U937 cells to cultured human ECs.


CONCLUSIONS
Human ECs express PPARalpha, a potentially important regulator of atherogenesis through its transcriptional control of VCAM-1 gene expression. Such findings also have implications regarding the clinical use of lipid-lowering agents, like fibric acids, which can activate PPARalpha.
Marx
N
N
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division and the Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sukhova
G K
GK
Collins
T
T
Libby
P
P
Plutzky
J
J
D000924:Anticholesteremic Agents / Q000494:pharmacology; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000737:chemistry / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology / Q000502:physiology; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D000924:Anticholesteremic Agents; D000960:Hypolipidemic Agents; D016328:NF-kappa B; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C006253:pirinixic acid; D011345:Fenofibrate