Molecular epidemiology; New but impressive.

Molecular epidemiology is a subdivision of medical science and epidemiology that emphases on the involvement of potential environmental and genetic risk factors, recognized at the molecular level, to the etiology and avoidance of sickness through populations. This arena has developed from the combination of molecular biology and traditional epidemiological research. Molecular epidemiology can improve our knowledge about the precise pathogenesis of disease through recognizing particular pathways that affect the risk of developing the disease.

Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis.

Although much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic pathways that counteract these events. Here we identified NOTCH1 as an antagonist of endothelial cell (EC) activation. NOTCH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high-fat diet.

Systemic inflammation, intestine, and paraoxonase-1.

Serum paraoxonase 1 (PON1) has been shown to act as an important guardian against cellular damage from oxidized lipids in low-density lipoprotein (LDL), plasma membrane, against toxic agents such as pesticide residues including organophosphates and against bacterial endotoxin. PON1 associated with circulating high-density lipoprotein (HDL) has the ability to prevent the generation of pro inflammatory oxidized phospholipids by reactive oxygen species. The activities of the HDL-associated PON1 and several other anti-inflammatory factors in HDL are in turn negatively regulated by these oxidized lipids.

HDL inhibits the effects of oxidized phospholipids on endothelial cell gene expression via multiple mechanisms.

Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phospholcholine (OxPAPC) and its component phospholipids accumulate in atherosclerotic lesions and regulate the expression of >1,000 genes, many proatherogenic, in human aortic endothelial cells (HAECs). In contrast, there is evidence in the literature that HDL protects the vasculature from inflammatory insult. We have previously shown that in HAECs, HDL attenuates the expression of several proatherogenic genes regulated by OxPAPC and 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine.

Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma.

The apoA-I mimetic peptide L-4F [(Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2) synthesized from all L-amino acids] has shown potential for the treatment of a variety of diseases. Here, we demonstrate that LDL promotes association between L-4F and HDL. A 2- to 3-fold greater association of L-4F with human HDL was observed in the presence of human LDL as compared with HDL by itself.

Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1.

Rationale: Oxidized palmitoyl arachidonyl phosphatidylcholine (Ox-PAPC) accumulates in atherosclerotic lesions, is proatherogenic, and influences the expression of more than 1000 genes in endothelial cells.

Objective: To elucidate the major pathways involved in Ox-PAPC action, we conducted a systems analysis of endothelial cell gene expression after exposure to Ox-PAPC.

Methods And Results: We used the variable responses of primary endothelial cells from 149 individuals exposed to Ox-PAPC to construct a network that consisted of 11 groups of genes, or modules.

Chronic inflammatory disorders and accelerated atherosclerosis: chronic kidney disease.

Increasing evidence points to the fact that plasma HDL cholesterol levels do not always accurately predict HDL function including reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of our innate immune system. HDL is anti inflammatory in healthy individuals in the absence of systemic oxidative stress and inflammation.

The effect of HDL mimetic peptide 4F on PON1.

Several lines of evidence indicate that serum paraoxonase 1 (PON1) acts as an important guardian against cellular damage from oxidized lipids in plasma membrane, in low-density lipoprotein (LDL), against bacterial endotoxin and against toxic agents such as pesticide residues including organophosphates. In circulation, the high-density lipoprotein (HDL)-associated PON1 has the ability to prevent the formation of proinflammatory oxidized phospholipids. These oxidized phospholipids negatively regulate the activities of the HDL-associated PON1 and several other anti-inflammatory factors in HDL.

Proatherogenic high-density lipoprotein, vascular inflammation, and mimetic peptides.

Atherosclerosis is an example of an inflammatory disorder. During the acute phase and under inflammatory conditions, high-density lipoprotein (HDL), which is normally anti-inflammatory, can become proinflammatory. Reactive oxygen species generated by several enzyme systems can modify phospholipids and sterols, producing oxidized phospholipids and oxidized sterols that reduce the capacity of HDL to protect against undesirable oxidative modifications of molecules.