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      Association between high-density lipoprotein-cholesterol and hypertension in relation to circulating CD34-positive cell levels

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          Abstract

          Background

          Although high-density lipoprotein-cholesterol (HDL) level is inversely correlated with cardiovascular events, HDL is also reported to be positively associated with hypertension, which is a known endothelial impairment factor. Since HDL mediates important protective actions on the vascular endothelium by increasing the number of circulating endothelial progenitor cells (CD34-positive cells), the level of circulating CD34-positive cells should influence the association between HDL and hypertension.

          Methods

          To investigate the association between HDL and hypertension in relation to the level of circulating CD34-positive cells, we conducted a cross-sectional study of 477 elderly men aged 60–69 years who participated in general health checkup.

          Results

          HDL was found to be significantly positively associated with hypertension in subjects with a high level of circulating CD34-positive cells, while no significant association was observed for subjects with low circulating CD34-positive cells. Known cardiovascular risk factors adjusted odds (ORs) and 95% confidence intervals (CIs) of hypertension for increments of one standard deviation (SD) in HDL (13.8 mg/dL) were 1.44 (1.06, 1.96) for subjects with a high level of circulating CD34-positive cells and 0.87 (0.63, 1.19) for subjects with low circulating CD34-positive cells. We also revealed a significant association between HDL level and CD34-positive cell level on hypertension, with fully adjusted p values for the effect of this interaction on hypertension at 0.022.

          Conclusions

          Independent of known cardiovascular risk factors, HDL was found to be positively associated with hypertension in subjects with a high level of circulating CD34-positive cells but not for subjects with low circulating CD34-positive cells.

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          Most cited references30

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          Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.

          Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow-derived circulating endothelial progenitor cells (EPCs). The regulation of EPCs in patients with coronary artery disease (CAD) is unclear at present. Therefore, we determined the number and functional activity of EPCs in 45 patients with CAD and 15 healthy volunteers. The numbers of isolated EPCs and circulating CD34/kinase insert domain receptor (KDR)-positive precursor cells were significantly reduced in patients with CAD by approximately 40% and 48%, respectively. To determine the influence of atherosclerotic risk factors, a risk factor score including age, sex, hypertension, diabetes, smoking, positive family history of CAD, and LDL cholesterol levels was used. The number of risk factors was significantly correlated with a reduction of EPC levels (R=-0.394, P=0.002) and CD34-/KDR-positive cells (R=-0.537, P<0.001). Analysis of the individual risk factors demonstrated that smokers had significantly reduced levels of EPCs (P<0.001) and CD34-/KDR-positive cells (P=0.003). Moreover, a positive family history of CAD was associated with reduced CD34-/KDR-positive cells (P=0.011). Most importantly, EPCs isolated from patients with CAD also revealed an impaired migratory response, which was inversely correlated with the number of risk factors (R=-0.484, P=0.002). By multivariate analysis, hypertension was identified as a major independent predictor for impaired EPC migration (P=0.043). The present study demonstrates that patients with CAD revealed reduced levels and functional impairment of EPCs, which correlated with risk factors for CAD. Given the important role of EPCs for neovascularization of ischemic tissue, the decrease of EPC numbers and activity may contribute to impaired vascularization in patients with CAD. The full text of this article is available at http://www.circresaha.org.
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            Evidence for circulating bone marrow-derived endothelial cells.

            It has been proposed that hematopoietic and endothelial cells are derived from a common cell, the hemangioblast. In this study, we demonstrate that a subset of CD34(+) cells have the capacity to differentiate into endothelial cells in vitro in the presence of basic fibroblast growth factor, insulin-like growth factor-1, and vascular endothelial growth factor. These differentiated endothelial cells are CD34(+), stain for von Willebrand factor (vWF), and incorporate acetylated low-density lipoprotein (LDL). This suggests the possible existence of a bone marrow-derived precursor endothelial cell. To demonstrate this phenomenon in vivo, we used a canine bone marrow transplantation model, in which the marrow cells from the donor and recipient are genetically distinct. Between 6 to 8 months after transplantation, a Dacron graft, made impervious to prevent capillary ingrowth from the surrounding perigraft tissue, was implanted in the descending thoracic aorta. After 12 weeks, the graft was retrieved, and cells with endothelial morphology were identified by silver nitrate staining. Using the di(CA)n and tetranucleotide (GAAA)n repeat polymorphisms to distinguish between the donor and recipient DNA, we observed that only donor alleles were detected in DNA from positively stained cells on the impervious Dacron graft. These results strongly suggest that a subset of CD34+ cells localized in the bone marrow can be mobilized to the peripheral circulation and can colonize endothelial flow surfaces of vascular prostheses.
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              Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells.

              Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34(-)Flt3(-) KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34(-)Flt3(-) KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the modulation of angiocrine factors, with Akt-mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs.
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                Author and article information

                Contributors
                +81-95-819-2523 , shimizuyuji@nagasaki-u.ac.jp
                fluctuat_nec_mergitur_j18@yahoo.co.jp
                jun_koyamatsu@yahoo.co.jp
                yhirotomo@yahoo.co.jp
                nmako@hotmail.com
                ko-kado@remus.dti.ne.jp
                shin-ya@nagasaki-u.ac.jp
                tmaeda@nagasaki-u.ac.jp
                Journal
                J Physiol Anthropol
                J Physiol Anthropol
                Journal of Physiological Anthropology
                BioMed Central (London )
                1880-6791
                1880-6805
                15 June 2017
                15 June 2017
                2017
                : 36
                : 26
                Affiliations
                [1 ]ISNI 0000 0000 8902 2273, GRID grid.174567.6, Department of Community Medicine, , Nagasaki University Graduate School of Biomedical Sciences, ; Nagasaki, Japan
                [2 ]Department of Cardiovascular Disease Prevention, Osaka Center for Cancer and Cardiovascular Disease Prevention, Osaka, Japan
                [3 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Research and Clinical Center for Yusho and Dioxin, , Kyusyu University, ; Fukuoka, Japan
                [4 ]ISNI 0000 0000 8902 2273, GRID grid.174567.6, Department of Island and Community Medicine, , Nagasaki University Graduate School of Biomedical Sciences, ; Nagasaki, Japan
                Author information
                http://orcid.org/0000-0002-3381-9288
                Article
                143
                10.1186/s40101-017-0143-9
                5472883
                28619079
                a4dfa481-bf8b-4504-b027-1345a7b590df
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 December 2016
                : 7 June 2017
                Funding
                Funded by: Grants-in-Aids for Scientific Research from the Japan Society for the Promotion of Science
                Award ID: 25291107
                Award Recipient :
                Funded by: Grants-in-Aids for Scientific Research from the Japan Society for the Promotion of Science
                Award ID: 15K07243
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © The Author(s) 2017

                Anthropology
                hdl-cholesterol,circulating cd34-positive cell,hypertension
                Anthropology
                hdl-cholesterol, circulating cd34-positive cell, hypertension

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