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Padfield G.J.,British Heart Foundation Center for Cardiovascular Science | Tura-Ceide O.,University of Edinburgh | Freyer E.,British Heart Foundation Center for Cardiovascular Science | Barclay G.R.,University of Edinburgh | And 3 more authors.
Open Heart | Year: 2014

Objective: Circulating CD34+CD45- cell concentrations are increased in patients with coronary artery disease, however their pathophysiological significance is unknown. We determined CD34+CD45- cell concentrations following percutaneous coronary intervention (PCI) in order to explore their role in acute vascular injury. Methods: In a prospective time-course analysis, we quantified using flow cytometry circulating CD34+CD45- cells, traditional CD34+VEGFR-2+ putative endothelial progenitor cells (EPCs), CD14+ VEGFR- 2+Tie-2+ angiogenic monocytes and intercellular adhesion molecule expression (CXCR-4 and CD18) in patients, before and during the first week following diagnostic angiography (n=13) or PCI (n=23). Vascular endothelial growth factor-A (VEGF-A) and C reactive protein (CRP) were quantified by ELISA. Results: Unlike diagnostic angiography, PCI increased circulating neutrophil and CRP concentrations at 24 and 48 h, respectively (p<0.002 for both). CD34+CD45- cell concentrations were unaffected by angiography (p>0.4), but were transiently increased 6 h following PCI (median (IQR) 0.93 (0.43-1.49) vs 1.51 (0.96-2.15)×106 cells/L; p=0.01), returning to normal by 24 h. This occurred in the absence of any change in serum VEFG-A concentration, adhesion molecule expression on CD34+ cells, or mobilisation of traditional EPCs or angiogenic monocytes (p>0.1 for all). Conclusions: PCI transiently increases circulating CD34+CD45- cells, without increasing CD34+ adhesion molecule expression or VEGF-A concentrations, suggesting that CD34+CD45- cells may be mobilised from the vessel wall directly as a result of mechanical injury. Traditional putative EPC and angiogenic monocytes are unaffected by PCI, and are unlikely to be important in the acute response to vascular injury. © 2014, BMJ Publishing Group. All rights reserved.


Kipari T.,British Heart Foundation Center for Cardiovascular Science | Kipari T.,Queens Medical Research Institute | Hadoke P.W.F.,British Heart Foundation Center for Cardiovascular Science | Iqbal J.,British Heart Foundation Center for Cardiovascular Science | And 18 more authors.
FASEB Journal | Year: 2013

11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11β- HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11β-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosisprone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11β-HSD1 inhibitor or crossed with 11β-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11β-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM- 1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11β- HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11β-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11β-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.- Kipari, T., Hadoke, P. W. F., Iqbal, J., Man, T. Y., Miller, E., Coutinho, A. E., Zhang, Z., Sullivan, K. M., Mitic, T., Livingstone, D. E. W., Schrecker, C., Samuel, K., White, C. I., Bouhlel, M. A., Chinetti- Gbaguidi, G., Staels, B., Andrew, R., Walker, B. R., Savill, J. S., Chapman, K. E., Seckl, J. R. 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow- derived cells reduces atherosclerosis. FASEB J. 27, 1519-1531 (2013). www.fasebj.org.


PubMed | British Heart Foundation Center for Cardiovascular Science and University of Edinburgh
Type: Journal Article | Journal: Open heart | Year: 2014

Circulating CD34(+)CD45(-) cell concentrations are increased in patients with coronary artery disease, however their pathophysiological significance is unknown. We determined CD34(+)CD45(-) cell concentrations following percutaneous coronary intervention (PCI) in order to explore their role in acute vascular injury.In a prospective time-course analysis, we quantified using flow cytometry circulating CD34(+)CD45(-) cells, traditional CD34(+)VEGFR-2(+) putative endothelial progenitor cells (EPCs), CD14(+) VEGFR(-) 2(+)Tie-2(+) angiogenic monocytes and intercellular adhesion molecule expression (CXCR-4 and CD18) in patients, before and during the first week following diagnostic angiography (n=13) or PCI (n=23). Vascular endothelial growth factor-A (VEGF-A) and C reactive protein (CRP) were quantified by ELISA.Unlike diagnostic angiography, PCI increased circulating neutrophil and CRP concentrations at 24 and 48h, respectively (p<0.002 for both). CD34(+)CD45(-) cell concentrations were unaffected by angiography (p>0.4), but were transiently increased 6h following PCI (median (IQR) 0.93 (0.43-1.49) vs 1.51 (0.96-2.15)10(6)cells/L; p=0.01), returning to normal by 24h. This occurred in the absence of any change in serum VEFG-A concentration, adhesion molecule expression on CD34(+) cells, or mobilisation of traditional EPCs or angiogenic monocytes (p>0.1 for all).PCI transiently increases circulating CD34(+)CD45(-) cells, without increasing CD34(+) adhesion molecule expression or VEGF-A concentrations, suggesting that CD34(+)CD45(-) cells may be mobilised from the vessel wall directly as a result of mechanical injury. Traditional putative EPC and angiogenic monocytes are unaffected by PCI, and are unlikely to be important in the acute response to vascular injury.

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