ABSTRACT
OBJECTIVE: Chronic infection has long been postulated as a stimulus for atherogenesis. Pseudomonas aeruginosa infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression. METHODS AND RESULTS: Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC. CONCLUSION: 3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
Subject(s)
4-Butyrolactone/analogs & derivatives , Aryldialkylphosphatase/metabolism , Endothelium, Vascular/metabolism , Homoserine/analogs & derivatives , Phospholipids/pharmacology , Quorum Sensing , Stress, Physiological/drug effects , 4-Butyrolactone/pharmacology , Aorta/cytology , Aorta/metabolism , Apoptosis/drug effects , Apoptosis/physiology , Aryldialkylphosphatase/antagonists & inhibitors , Aryldialkylphosphatase/drug effects , Cells, Cultured , Endothelium, Vascular/cytology , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Homoserine/pharmacology , Humans , Lipoproteins, LDL/metabolism , Oxidation-Reduction , RNA, Small Interfering/pharmacology , Stress, Physiological/physiologyABSTRACT
BACKGROUND: Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice. METHODS AND RESULTS: Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2- to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively. CONCLUSIONS: Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.
