Peroxisome proliferator-activated receptors: how their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis.
Peroxisome proliferator-activated receptors (PPARs) alpha (alpha), beta/delta (beta/delta), and gamma (gamma) are members of the nuclear receptor superfamily, which also includes the estrogen, androgen, and glucocorticoid receptors. Recent evidence suggests that PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation in various tissues; however, the mechanisms involved are not completely understood. Anti-diabetic drugs, called glitazones, can selectively activate PPARgamma, and hypolipidemic drugs, called fibrates, can weakly activate PPARalpha. Both classes of drugs can decrease insulin resistance and dyslipidemias, which also makes them attractive for treating the metabolic syndrome. The metabolic syndrome exhibits a constellation of risk factors for atherosclerosis that include obesity, insulin resistance, dyslipidemias, and hypertension. Interestingly, all three PPARs are present in macrophages and can therefore have a profound effect on several disease processes, including atherosclerosis. Macrophages are key players in atherosclerotic lesion development. Currently, the first line of defense in reducing the risk of atherosclerosis is aimed at lowering low-density lipoproteins (LDL) and raising high-density lipoproteins (HDL), but a large percentage of patients on statins still succumb to coronary artery disease. However, with the development of drugs selectively activating PPARs, a new arsenal of drugs specifically targeting to the macrophage/foam cell may potentially have a profound impact on how we treat cardiovascular disease.
Li
Andrew C
AC
Department of Cellular & Molecular Medicine, University of California-San Diego, La Jolla, CA 92093-0682, USA. acli@ucsd.edu
Palinski
Wulf
W
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008264:Macrophages / Q000187:drug effects*; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects* / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects
D002317:Cardiovascular Agents; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear