Anti-atherogenic role of Peroxisome Proliferator Activated Receptor ligands

Two families of peroxisome proliferating-activated receptor (PPAR) ligands are utilized clinically to address abnormalities of blood-borne cardiovascular risk factors. PPAR-a ligands, the fibrates, lower plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol leading to positive outcomes in clinical trials such as the Veterans Affairs HDL Intervention Trial. PPAR-? ligands, the recently introduced family of thiazolidinediones, act as insulin sensitizers to alleviate the hyperglycemia of insulin resistant states such as Type 2 diabetes. The primary aim of treating the cardiovascular risk factors is to reduce the burden of cardiovascular disease, mostly atherosclerotic vascular disease. Considerable evidence is emerging that PPAR ligands can exert anti-atherogenic activity. Although the agents acting on their target nuclear receptors are primarily regulators of gene transcription it may be that some actions are independent of gene transcription and represent direct inhibition of atherogenic signalling pathways in the vasculature. The direct actions including inhibition of vascular smooth muscle cell proliferation and inhibition of glycosaminoglycan elongation on proteoglycans, the latter leading to reduced low-density lipoprotein (LDL) binding, provide in vitro examples of antiatherogenic actions.