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      Long-term, regular remote ischemic preconditioning improves endothelial function in patients with coronary heart disease

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          Abstract

          Remote ischemic preconditioning (RIPre) can prevent myocardial injury. The purpose of this study was to assess the beneficial effects of long-term regular RIPre on human arteries. Forty patients scheduled for coronary artery bypass graft (CABG) surgery were assigned randomly to a RIPre group (n=20) or coronary heart disease (CHD) group (n=20). Twenty patients scheduled for mastectomy were enrolled as a control group. RIPre was achieved by occluding arterial blood flow 5 min with a mercury sphygmomanometer followed by a 5-min reperfusion period, and this was repeated 4 times. The RIPre procedure was repeated 3 times a day for 20 days. In all patients, arterial fragments discarded during surgery were collected to evaluate endothelial function by flow-mediated dilation (FMD), CD34 + monocyte count, and endothelial nitric oxide synthase (eNOS expression). Phosphorylation levels of STAT-3 and Akt were also assayed to explore the underlying mechanisms. Compared with the CHD group, long-term regular RIPre significantly improved FMD after 20 days (8.5±2.4 vs 4.9±4.2%, P<0.05) and significantly reduced troponin after CABG surgery (0.72±0.31 and 1.64±0.19, P<0.05). RIPre activated STAT-3 and increased CD34 + endothelial progenitor cell counts found in arteries. Long-term, regular RIPre improved endothelial function in patients with CHD, possibly due to STAT-3 activation, and this may have led to an increase in endothelial progenitor cells.

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          Most cited references23

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          Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization.

          Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis. We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.
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            Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion

            The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening.
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              Expression of the CD34 gene in vascular endothelial cells.

              All seven of a set of CD34 monoclonal antibodies that recognize epitopes on an approximately 110 Kd glycoprotein on human hemopoietic progenitor cells also bind to vascular endothelium. Capillaries of most tissues are CD34 positive, as are umbilical artery and, to a lesser extent, vein, but the endothelium of most large vessels and the endothelium of placental sinuses are not. Angioblastoma cells and parafollicular mesenchymal cells in fetal skin are also CD34 positive, as are some stromal elements. An approximately 110 Kd protein can be identified by Western blot analysis with CD34 antibodies in detergent extracts of freshly isolated umbilical vessel endothelial cells, and CD34 mRNA is present in cultured umbilical vein cells as well as other tissues rich in vascular endothelium (breast, placenta). These data indicate that the binding of CD34 antibodies to vascular endothelium is to the CD34 gene product, and not to crossreactive epitopes. Despite the presence of CD34 mRNA in cultured, proliferating endothelial cells, the latter do not bind CD34 antibodies. In addition, CD34 antigen cannot be upregulated by growth factors. We conclude that under these conditions, CD34 protein is downregulated or processed into another form that is unreactive with CD34 antibodies. Electron microscopy of umbilical artery, breast, and kidney capillary vessels reveals that in all three sites, CD34 molecules are concentrated on membrane processes, many of which interdigitate between adjacent endothelial cells. However, well-established endothelial cell contacts with tight junctions are CD34 negative. CD34 may function as an adhesion molecule on both endothelial cells and hematopoietic progenitors.
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                Author and article information

                Journal
                Braz J Med Biol Res
                Braz. J. Med. Biol. Res
                Brazilian Journal of Medical and Biological Research
                Associação Brasileira de Divulgação Científica
                0100-879X
                1414-431X
                28 April 2015
                June 2015
                : 48
                : 6
                : 568-576
                Affiliations
                Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
                Author notes
                Correspondence: Jinying Zhang, E-mail: <x201017liangying@ 123456126.com>.
                Article
                10.1590/1414-431X20144452
                4470317
                25923462
                0bc2b62f-c37e-4135-bf4a-d31112c09d98

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 October 2014
                : 19 December 2014
                Page count
                Figures: 5, Tables: 3, References: 33, Pages: 9
                Categories
                Clinical Investigation

                remote ischemic preconditioning,endothelial function,coronary heart disease,stat-3

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