Impairment of circulating endothelial progenitors in Down syndrome

<p>Abstract</p> <p>Background</p> <p>Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome.</p> <p>Methods</p> <p>Circulating endothelial progenitors of Down syndrome affected individuals were isolated, <it>in vitro </it>cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1α plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of <it>CXCL12 </it>gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis.</p> <p>Results</p> <p>We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1α plasma levels and their progenitors had a reduced expression of SDF-1α encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells.</p> <p>Conclusions</p> <p>Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.</p

Reduction in infarct size by the prostacyclin analogue iloprost (ZK 36374) after experimental coronary artery occlusion-reperfusion.

In this study we attempted to determine whether administration of iloprost (ZK 36374), a chemically stable prostacyclin analogue, would reduce infarct size after experimental coronary artery occlusion and reperfusion. One hour of coronary artery occlusion was performed in 28 open-chest, anesthetized rabbits++, followed by 5 hours of reperfusion. Two minutes after occlusion, 99mTc-labeled albumin microspheres were injected into the left atrium for later assessment of the area at risk of infarction. Fifteen minutes after occlusion animals were randomly assigned to either the treatment group (iloprost, 1.2 micrograms/kg/min intravenously for 6 hours; n = 14) or the control group (n = 14). In vitro platelet aggregation was inhibited in rabbits receiving iloprost. In 10 rabbits (five treated and five control) regional myocardial blood flow was also measured by means of differentially labeled radioactive microspheres. Infarct size was significantly smaller in treated rabbits (53.6 +/- 4.1% of the risk zone vs 89.4 +/- 3.8% in control rabbits; p less than 0.001). Flow to the nonischemic myocardium was higher in treated animals, that is, 1.87 +/- 0.20 ml/min/gm of tissue 50 minutes after occlusion and 1.90 +/- 0.20 ml/min/gm of tissue 4 hours after reperfusion, compared with 1.54 +/- 0.20 and 1.64 +/- 0.30 ml/min/gm of tissue, respectively, in control rabbits (p less than 0.01). Collateral flow to the ischemic region was not affected by the drug. Mean arterial blood pressure, heart rate, and pressure-rate product in treated rabbits were not significantly different from values in control rabbits. In conclusion, administration of iloprost reduced myocardial infarct size in this model of myocardial ischemia and reperfusion in absence of major hemodynamic effects