Platelet interaction with bioactive lipids formed by mild oxidation of low-density lipoprotein.
Oxidation of low-density lipoprotein (LDL) generates pro-inflammatory and pro-thrombotic mediators that play a crucial role in cardiovascular and inflammatory diseases. Mildly oxidized LDL (mox-LDL) and minimally modified LDL (mm-LDL) which escape the uptake of macrophage scavenger receptors accumulate in the atherosclerotic intima. Oxidatively modified LDL is also present within the electronegative LDL fraction in blood, which is elevated in patients at high risk for cardiovascular diseases. Mox-LDL and mm-LDL, but not native LDL are able to induce platelet shape change and aggregation. LDL oxidation generates lipids with platelet stimulatory properties such as lysophosphatidylcholine, certain oxidized phosphatidylcholine molecules, F(2)-isoprostanes and lysophosphatidic acid (LPA). Mox-LDL and mm-LDL are like a Trojan horse carrying these biologically active lipids and attacking cells through activation of physiological receptors and signaling mechanisms. LPA has been identified as the lipid responsible for platelet stimulation by mox-LDL, mm-LDL and also mox-HDL. These lipoproteins activate platelets by stimulating G-protein coupled LPA receptors and a Rho/Rho kinase signaling pathway leading to platelet shape change and subsequent aggregation. LPA-mediated platelet activation might contribute to arterial thrombus formation after rupture of atherosclerotic plaques and to the increased blood thrombogenicity of patients with cardiovascular diseases.
Siess
Wolfgang
W
Institute for Prevention of Cardiovascular Diseases, University of Munich, Germany. wolfgang.siess@med.uni-muenchen.de
D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology*; D008078:Cholesterol, LDL / Q000502:physiology*; D028441:F2-Isoprostanes / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology; D006801:Humans; D008055:Lipids / Q000502:physiology*; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000502:physiology; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000502:physiology; D015539:Platelet Activation; D015398:Signal Transduction
D008078:Cholesterol, LDL; D028441:F2-Isoprostanes; D008055:Lipids; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010713:Phosphatidylcholines; C032881:lysophosphatidic acid