IntroductionNeovascularization is necessary for repairing the damaged ischemic tissue such as myocardial infarct and ischemic limb. 1,2 Bone marrow (BM)-derived stem/progenitor cells play a pivotal role in repairing the destroyed vasculature in ischemic tissue by multistep processes of mobilization, recruitment to ischemic tissue, and adhesion to hypoxic endothelial cells. [3][4][5] Clinical reports demonstrated that intracoronary infusion of BM-derived cells may improve the outcome of patients with acute myocardial infarction. 6,7 However, therapeutic efficacy was limited because the efficiency of targeting BM-derived cells to ischemic area is low. Thus, the recruitment of BM-derived cells into injured foci should be improved for repairing ischemic tissues efficiently.Hypoxia-inducible factor-1 (HIF-1) is a master transcription factor for adaptive responses to hypoxia and ischemia. 8,9 HIF-1 regulates more than 60 genes affecting cell survival, metabolism, and vessel formation such as vascular endothelial growth factor (VEGF), placental growth factor, and basic fibroblast growth factor. 8 HIF-1 is a heterodimer consisting of a constitutive HIF-1 and a hypoxia-induced HIF-1␣, which is mainly regulated by ubiquitination and proteasomal degradation. HIF-1␣ protein synthesis, however, is also up-regulated by growth factors such as insulin, epidermal growth factor, and insulin-like growth factor-1 and is inhibited by tumor suppressors. 9,10 Ang-1 is an endothelial growth factor binding to the Tie2 receptor and induces Tie2 phosphorylation. 11 Ang-1 plays essential roles in regulating vascular development, maintenance of endothelial integrity, and vessel maturation. [12][13][14][15] We recently reported the new role of Ang-1 as a cell primer. 16 Priming of progenitor cells means the short-term stimulation of the cells with cytokine to improve the therapeutic potential. Primed BM-derived progenitor cells (BMPCs) with Ang-1 increased the expression of adhesion molecules and commitment to endothelial lineage leading to improved engraftment into ischemic tissue and vasculogenesis. 16 In this study, we investigated the effect of locally administered Ang-1 on the recruitment of BMPCs to the ischemic tissue. We showed that Ang-1 is a critical stimulator of HIF-1␣ and stromal cell-derived factor 1 (SDF-1), and thus enhances the recruitment of the BMPCs to ischemic foci. We found a new action mechanism of Ang-1 in vasculogenesis, which modulates mammalian target of rapamycin (mTOR) activation on hypoxia, leading to HIF-1␣ protein synthesis and SDF-1 accumulation in hypoxic endothelium. The intermediate mechanisms that transmit the Ang-1 signal down to the mTOR/HIF-1␣/SDF-1 axis were the induction of colocalization of Tie2 receptor and integrin-linked kinase (ILK) at the cell membrane and the enhanced binding between them. We also demonstrated in vivo that Ang-1 facilitated functional incorporation of BMPCs into ischemic endothelium and increased For personal use only. on May 12, 2018. by guest www.bloodjournal.org From neova...
Despite the greater reduction of platelet reactivity by addition of cilostazol to conventional DAT, TAT did not show superiority in reducing the composite of adverse cardiovascular outcomes after DES implantation. (The Efficacy of CILostazol ON Ischemic Complications After DES Implantation [CILON-T]; NCT00776828).
In this study, the rate of post-treatment thromboembolism was not significantly different among the treatment groups; however, operative treatment tended towards less post-treatment thromboembolism than other treatment groups.
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