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Aims The lectin-like oxLDL receptor-1 (LOX-1) promotes endothelial uptake of oxidized low-density lipoprotein (oxLDL) and plays an important role in atherosclerosis and acute coronary syndromes (ACS). However, its role in arterial thrombus formation remains unknown. We investigated whether LOX-1 plays a role in arterial thrombus formation in vivo at different levels of oxLDL using endothelial-specific LOX-1 transgenic mice (LOX-1TG) and a photochemical injury thrombosis model of the carotid artery. Methods and results In mice fed a normal chow diet, time to arterial occlusion was unexpectedly prolonged in LOX-1TG as compared to WT. In line with this, tissue factor (TF) expression and activity in carotid arteries of LOX-1TG mice were reduced by half. This effect was mediated by activation of octamer transcription factor 1 (Oct-1) leading to upregulation of the mammalian deacetylase silent information regulator-two 1 (SIRT1) via binding to its promoter and subsequent inhibition of NF-κB signaling. In contrast, intravenous injection of oxLDL as well as high cholesterol diet for 6 weeks led to a switch from the Oct-1/SIRT1 signal transduction pathway to the ERK1/2 pathway and in turn to an enhanced thrombotic response with shortened occlusion time. Conclusions Thus, LOX-1 differentially regulates thrombus formation in vivo depending on the degree of activation by oxLDL. At low oxLDL levels LOX-1 activates the protective Oct-1/SIRT1 pathway, while at higher levels of the lipoprotein switches to the thrombogenic ERK1/2 pathway. These findings may be important for arterial thrombus formation in ACS and suggest that SIRT1 may represent a novel therapeutic target in this context.

Increased cyclic stretch to the vessel wall, as observed in hypertension, leads to endothelial dysfunction through increased free radical production and reduced nitric oxide bioavailability. Genetic deletion of the adaptor protein p66 Shc protects mice against age-related and hyperglycemia-induced endothelial dysfunction, as well as atherosclerosis and stroke. Furthermore, p66 Shc mediates vascular dysfunction in hypertensive mice. However, the direct role of p66 Shc in mediating mechanical force–induced free radical production is unknown; thus, we studied the effect of cyclic stretch on p66 Shc activation in primary human aortic endothelial cells and aortic endothelial cells isolated from normotensive and hypertensive rats. Exposure of human aortic endothelial cells to cyclic stretch led to a stretch- and time-dependent p66 Shc phosphorylation at Ser36 downstream of integrin α5β1 and c-Jun N-terminal kinase. In parallel, nicotinamide adenine dinucleotide phosphate oxidase activation, as well as production of reactive oxygen species, increased, whereas nitric oxide bioavailability decreased. Silencing of p66 Shc blunted stretch-increased superoxide anion production and nicotinamide adenine dinucleotide phosphate oxidase activation and restored nitric oxide bioavailability. In line with the above, activation of p66 Shc increased in isolated aortic endothelial cells of spontaneously hypertensive rats compared with normotensive ones. Pathological stretch by activating integrin α5β1 and c-Jun N-terminal kinase phosphorylates p66 Shc at Ser36, augments reactive oxygen species production via nicotinamide adenine dinucleotide phosphate oxidase, and in turn reduces nitric oxide bioavailability. This novel molecular pathway may be relevant for endothelial dysfunction and vascular disease in hypertension.

Objective The interplay between oxidative stress and inflammation is crucial in the pathogenesis of atherosclerosis. The adaptor protein p66Shc is implicated in atherogenesis and oxidative stress related responses in animal models of diseases. However, its role in humans remains to be defined. In this study, we hypothesized that expression of p66Shc increases in peripheral blood monocytes of patients affected by acute coronary syndromes (ACS). Methods Male subjects aged 59 ± 4 (mean ± SD) years admitted for cardiac catheterization were subdivided in three groups: (a) no local stenosis for the control group, (b) at least one stenosis ≥75% in either left, circumflex or right coronary artery for the coronary artery disease (CAD) group or (c) ST-elevation/non-ST-elevation myocardial infarction for the ACS group. Monocytes were isolated from whole blood and p66Shc RNA levels were determined by quantitative real time PCR. Results p66Shc RNA levels were increased in ACS patients as compared to CAD (p = 0.007) and controls (p = 0.0249). Furthermore, malondialdehyde (MDA) and C-reactive protein (CRP) were increased in plasma of ACS patients. Levels of MDA correlated positively to p66Shc (r = 0.376, p = 0.01). Our data demonstrate increased p66Shc levels in monocytes of ACS but not CAD patients. Conclusion This study suggests an involvement of p66Shc in the transition of a stable CAD to an ACS patient. p66Shc was associated with states of increased oxidative stress. Further work is needed to understand whether p66Shc may represent a possible pharmacological target or whether it represents an interesting novel biomarker.