Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.
Peroxisome proliferator-activated receptors (PPAR)alpha, gamma and beta/delta belong to the nuclear receptor family of ligand-activated transcription factors. PPARs heterodimerize with the retinoid X receptor (RXR) and then act as transcription factors to modulate the function of many target genes. PPARalpha, gamma and beta/delta subtypes have significant differences in their ligand and gene specificities. PPARalpha is activated by polyunsaturated fatty acids and by fibrate drugs (fenofibrate and gemfibrozil) and controls expression of genes involved in lipid metabolism. PPARgamma is activated by fatty acid derivatives, such as hydroxyoctadecadienoic acid (HODEs), prostaglandin derivatives, such as 15-deoxy-Delta12,14-prostaglandin J2, and thiazolidinedione (glitazone) drugs, such as pioglitazone and rosiglitazone. PPARgamma is a key regulator of glucose homeostasis and adipogenesis. PPARbeta/delta ligands include polyunsaturated fatty acids, prostaglandins and synthetic compounds and stimulate fatty acid oxidation. All PPARs are expressed in vascular cells where they exert antiatherogenic, anti-inflammatory and vasculoprotective actions. Activators of PPARalpha (fibrates) and PPARgamma (thiazolidinediones or glitazones) antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. PPAR agonists slightly reduce blood pressure are cardio-protective and correct vascular structure and endothelial dysfunction in experimental models of hypertension. Because of these beneficial effects, activators of PPARs may have therapeutic potential in the prevention of cardiovascular disease beyond their actions on carbohydrate and lipid metabolism. The present chapter focuses on the role of PPARs in vascular biology and discusses the clinical implications of using PPAR agonists in the management of vascular disease.
Touyz
Rhian M
RM
Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada. rtouyz@uottawa.ca
Schiffrin
Ernesto L
EL
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002995:Clofibric Acid / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D002995:Clofibric Acid