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<h3>Introduction</h3> Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in patients with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. DNA damage has been recognised as an important contributor to CVD. Our aim was to investigate whether EPC from smokers and COPD patients are dysfunctional, and the role of DNA damage pathways in mediating endothelial dysfunction in these patients. <h3>Methods</h3> To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples of healthy non-smokers, healthy smokers and COPD patients. Endothelial senescence was measured by senescence-associated β-galactosidase (SA-β-Gal) activity. Expression of sirtuin (SIRT)-1, p16, p21, γ-H2AX and 53BP1 were measured by Western blotting and/or immunofluorescence confocal microscopy. SIRT1 activity was measured using a SIRT1 fluorescent activity assay kit. To investigate angiogenesis <i>in vivo</i>, BOEC were labelled with Vybrant DiI Cell-Labelling Solution, mixed with Matrigel and injected subcutaneously into the back of NOD. CB17-Prkdcscid/NcrCrl mice. Seven days later, the mice were sacrificed and the plugs were cryosectioned. <h3>Results</h3> BOEC from smokers and COPD patients showed increased DNA double-strand breaks (measured by γ-H2AX, 53BP1) and senescence (senescence associated-β-galactosidase activity, p16 and p21 levels) compared to non-smokers. Senescence negatively correlated with sirtuin-1 (SIRT1) expression and activity, a protein deacetylase that inhibits DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia-mutated (ATM) kinase resulted in up-regulation of SIRT1 expression and decreased senescence. Interestingly, treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or a selective ATM inhibitor rescued the senescent phenotype. Using the <i>in vivo</i> Matrigel plug assay, BOEC from COPD patients displayed reduced angiogenesis (capillary-like structures) and increased DNA damage, senescence and apoptosis (measured by 53BP1, p16, TUNEL and cleaved-caspase 3 staining) compared to non-smokers. <h3>Conclusions</h3> BOEC from smokers and COPD patients show reduced angiogenesis <i>in vivo </i>and display increased DNA damage and senescence, associated with reduced SIRT1 expression. These defects may contribute to endothelial dysfunction and cardiovascular events in smokers and COPD patients and could potentially constitute therapeutic targets for intervention.
No abstract is provided for this article.
Fully bioabsorbable scaffolds (BRS) are a novel approach that provides transient vessel support with drug delivery capability without the long-term limitations of the metallic drug-eluting stents (DES), such as permanent caging with or without malapposition. The technology has the potential to overcome many of the safety concerns associated with metallic DES, and possibly even convey further clinical benefit. Although the technology is still in its infancy, several devices have been tested in clinical trials and the initial results have been very promising. This review will discuss the emerging need for BRS, the theoretical advantages of this new technology over current generation metallic DES and review the status of the currently available BRS. In addition, we will discuss the ideal duration of bioresorption, the proven and potential clinical benefits and future perspectives of this rapidly progressing technology. (Circ J 2011; 75: 509-520)
No abstract is provided for this article.