Neutrophil-derived microparticles are released into the coronary circulation following percutaneous coronary intervention in acute coronary syndrome patients.

To evaluate (i) local coronary and systemic levels of microparticles (MP) in acute coronary syndrome (ACS) and stable angina pectoris (SAP) patients and (ii) their release after plaque disruption with percutaneous coronary intervention (PCI). MP are small vesicles originating from plasma membranes of cells after activation or apoptosis and are implicated in the pathogenesis of atherosclerosis. Neutrophils play a role in plaque destabilization and shed neutrophil-derived MP that have the potential to drive significant proinflammatory and thrombotic downstream effects. Eight ACS and eight SAP patients were included. Coronary sinus (CS) samples pre-intervention (CS1), 45 s following balloon angioplasty (CS2) and at 45 s intervals following stent deployment (CS3, CS4 and CS5), together with peripheral vein samples, pre- and post-PCI were analysed for neutrophil-derived (CD66b+), endothelial-derived (CD144+), platelet-derived (CD41a+), monocyte-derived (CD14+) and apoptotic (Annexin V+) MP. ELISA for interleukin (IL)-6, myeloperoxidase (MPO) and P-selectin was also performed. CD66b+ MP levels were similar in both groups pre-intervention. Post-PCI, CS levels rose significantly in ACS but not SAP patients (ACS area under the curve (AUC): 549 ± 83, SAP AUC: 24 ± 29, P<0.01). CS CD41a+, CD144+, CD14+ and Annexin V+ MP levels did not differ between groups. Acute neutrophil-derived MP release post-PCI occurs in ACS compared with stable patients, likely to be reflective of plaque MP content in vulnerable lesions

TNF-α inhibits trophoblast integration into endothelial cellular networks

Preeclampsia has been linked to shallow trophoblast invasion and failure of uterine spiral artery transformation. Interaction between trophoblast cells and maternal uterine endothelium is critically important for this remodelling. The aim of our study was to investigate the effect of TNF-α on the interactions of trophoblast-derived JEG-3 cells into capillary-like cellular networks. We have employed an in vitro trophoblast-endothelial cell co-culture model to quantify trophoblast integration into endothelial cellular networks and to investigate the effects of TNF-α. Controlled co-cultures were also treated with anti-TNF-α antibody (5 μg/ml) to specifically block the effect of TNF-α. The invasion was evaluated by performing quantitative PCR (Q-PCR) to analyse gene expression of matrix metalloproteinases-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, integrins (α1β1 and α6β4), plasminogen activator inhibitor (PAI)-1, E-cadherin and VE-cadherin. JEG-3 cell integration into endothelial networks was significantly inhibited by exogenous TNF-α. The inhibition was observed in the range of 0.2–5 ng/ml, to a maximum 56% inhibition at the highest concentration. This inhibition was reversed by anti-TNF-α antibody. Q-PCR analysis showed that mRNA expression of integrins α1β1 and MMP-2 was significantly decreased. VE-cadherin mRNA expression was significantly up-regulated (32–80%, p < 0.01) but its protein concentration in the cell lysates was significantly reduced (20–45%, p < 0.01). PAI-1, MMP-9, TIMP-1 and E-cadherin were not affected. In conclusion, TNF-α can inhibit trophoblast-like cells (JEG-3) integration into maternal endothelial cellular networks, and this process involves the inhibition of MMP-2 and a failure of integrins switch from α6β4 to α1β1. These molecular correlations reflect the changes identified in human preeclampsia

Telomere length in early childhood : early life risk factors and association with carotid intima-media thickness in later childhood

Background Reduced telomere length is a measure of biological aging that is predictive of cardiac events in adults, and has been mechanistically implicated in the onset and progression of atherosclerosis. We sought to describe the early life factors associated with leukocyte telomere length in early childhood, and to determine whether telomere length measured during early childhood is associated with arterial wall thickening later in childhood. Design A longitudinal birth cohort recruited antenatally in Sydney from 1997 to 1999. Methods Leukocyte telomere length was measured in 331 children at age 3.6 years (SD 1.0); of whom 268 children without diabetes had carotid intima-media thickness assessed by ultrasound at age 8 years. Results Male sex, younger paternal age and higher maternal body mass index were associated with shorter telomere length in early childhood, which in turn was associated with greater carotid intima-media thickness at age 8 years (standardised β = -0.159, P = 0.01). There was a graded association across quartiles of telomere length (Ptrend = 0.001) with the highest odds of elevated intima-media thickness (˃75th percentile) being in children with the shortest telomeres (odds ratio 4.00 (95% confidence interval 1.58 to 10.14) relative to those with the longest telomeres, P = 0.003). This association remained after adjustment for early life risk factors (Ptrend = 0.001). Conclusions Reduced telomere length in early childhood is independently associated with arterial wall thickness in later childhood, suggesting that reduced telomere length during early childhood may be a marker of vascular disease risk