Intimal smooth muscle cells as a target for peroxisome proliferator-activated receptor-gamma ligand therapy.
Activation of the nuclear receptor/transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), is a newly defined target for limiting vascular pathologies. PPARgamma is expressed in human and animal models of vascular disease, with particularly high levels being present in the cells of the neointimal microenvironment. In the present study, we show that intimal smooth muscle cells in vitro contain higher amounts of functional PPARgamma than medial smooth muscle cells. The PPARgamma ligand rosiglitazone more potently induced CD36 expression at low concentrations, and cell death by apoptosis at higher concentrations in intimal compared with medial smooth muscle cells. Intimal smooth muscle cells also contained high levels of cyclooxygenase-2 protein, and released a more diverse and larger amount of eicosanoids on arachidonic acid stimulation. Furthermore, when exogenous arachidonic acid was added, PPAR reporter gene activation was induced in a cyclooxygenase inhibitor-sensitive manner, an effect that correlated with an increase in CD36 expression. In summary, intimal smooth muscle cells contain functionally higher levels of PPARgamma, PPARgamma ligands have high- and low-potency targets in vascular smooth muscle cells, and cyclooxygenase can serve as a source of potential endogenous PPAR ligands. Intimal vascular smooth muscle cells therefore represent a potentially important target for the antiproliferative, and antiatherosclerotic actions of PPARgamma ligands.
Bishop-Bailey
David
D
Department of Cardiac, Vascular, and Inflammation Research, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK. d.bishop-bailey@qmul.ac.uk
Hla
Timothy
T
Warner
Timothy D
TD
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D018955:CD36 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016503:Drug Delivery Systems; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008024:Ligands; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology; D011453:Prostaglandins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017539:Tunica Intima / Q000166:cytology; D017540:Tunica Media / Q000378:metabolism
D018955:CD36 Antigens; D007527:Isoenzymes; D008024:Ligands; D011453:Prostaglandins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases