Rationale Ox-PAPC accumulates in atherosclerotic lesions, is pro-atherogenic, and influences the expression of over 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 consisting of 11 groups of genes or modules. Modules were enriched for a broad range of GO pathways, some of which have not been previously identified as major Ox-PAPC targets. Further validating our method of network construction, modules were consistent with relationships established by cell biology studies of Ox-PAPC effects on endothelial cells. This network provides novel hypotheses about molecular interactions, as well as candidate molecular regulators of inflammation and atherosclerosis. We validate several hypotheses based on network connections and genomic association. Our network analysis predicted that the hub gene CHAC1 was regulated by the ATF4 arm of the unfolded protein response pathway and here we showed that ATF4 directly activates an element in the CHAC1 promoter. We show that variation in basal levels of HMOX1 contribute to the response to Ox-PAPC, consistent with its position as a hub in our network. We also identified GPR39 as a regulator of HMOX1 levels and showed that it modulates the promoter activity of HMOX1. We further showed that OKL38/OSGN1, the hub gene in the blue module, is a key regulator of both inflammatory and anti-inflammatory molecules. Conclusions Our systems genetics approach has provided a broad view of the pathways involved in the response of endothelial cells to Ox-PAPC and also identified novel regulatory mechanisms.

Briot et al. show that inflammatory lipids deriving from a high-fat diet suppress NOTCH1 expression and signaling in adult arterial endothelium and propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of atherosclerosis.

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. In those with chronic illnesses such as renal failure however, HDL may become dysfunctional and actually promote inflammation. HDL may be thought of as a shuttle whose size can be estimated by HDL cholesterol levels. The content of the shuttle however, is what determines the anti inflammatory potential of HDL and can change from one, supporting reverse cholesterol transport to one that is less efficient in carrying out this function. Chronic kidney disease (CKD), and inflammatory disorder, is associated with development of accelerated atherosclerosis and premature death from coronary artery disease (CAD). Patients with CKD present with dyslipidemia, oxidative stress and systemic inflammation. Among the abnormalities in lipid metabolism in these patients is reduced levels and protective capacity of HDL. Recent studies have shown that HDL from patients with end stage renal disease is not capable of preventing LDL oxidation and that it induces monocyte migration in artery wall model systems. Treatment of plasma from these patients, with an HDL mimetic peptide improved the anti inflammatory properties of patient's HDL and made LDL more resistant to oxidative modification. Animal models of kidney disease also had proinflammatory HDL and treatment with the peptide mimetic improved markers of inflammation and anti inflammatory capacity of HDL. Whether HDL mimetic peptides will have therapeutic benefit in patients with renal failure will have to be determined in clinical studies.

No abstract

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. In animal models of dyslipidemia, diabetes, vascular inflammation, and chronic rejection, it is observed that reducing oxidative and inflammatory pressure will help HDL regain its protective role. One way to accomplish this is through the use of apolipoprotein A-I mimetic peptides, which remove oxidation products from lipoproteins and cell membranes, returning normal structure and function to low-density lipoprotein and HDL. These mimetic peptides markedly reduce atherosclerosis in animal models. Published studies of apolipoprotein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they have efficacy in a wide range of inflammatory conditions.