Darapladib and atherosclerotic plaque: should lipoprotein-associated phospholipase A2 be a therapeutic target?
There is great interest in developing a reliable measure of atherosclerotic disease activity that can serve as an index of response to antiatherosclerotic therapies. The epidemiologic relationship between lipid measures, most notably low-density lipoprotein cholesterol (LDL-C), and binary cardiovascular events has been confirmed in treatment trials reliably demonstrating a reduction in LDL-C translating into improved cardiovascular outcomes. Lipoprotein-associated phospholipase A2 (LpPLA2) is part of a family of lipases involved in the modification of lipids within the atheroma and may be a complimentary therapeutic target to the reduction of LDL-C in patients with advanced atherosclerosis. Darapladib is an orally available, specific inhibitor of LpPLA2 activity and has been shown to reduce lysophosphatidylcholine content and expression of multiple genes associated with macrophage and T-lymphocyte functioning, with considerable decrease in plaque and necrotic core area. Thus, this agent holds the hope of being a bona fide antiatherosclerotic therapy that can be gauged through blood measurement of LpPLA2 activity.
McCullough
Peter A
PA
Divisions of Cardiology, Nutrition and Preventive Medicine, William Beaumont Hospital, Beaumont Health Center, Royal Oak, MI 48073, USA. peteramccullough@gmail.com
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood* / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology; D001547:Benzaldehydes / Q000627:therapeutic use*; D006801:Humans; D010091:Oximes / Q000627:therapeutic use*; D016896:Treatment Outcome; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D010091:Oximes; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides