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Pitavastatin nanoparticle-engineered endothelial progenitor cells repair injured vessels

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      Abstract

      Endothelial progenitor cells (EPC) participate in vessel recovery and maintenance of normal endothelial function. Therefore, pitavastatin-nanoparticles (NPs)-engineered EPC may be effective in repairing injured vasculature. Pitavastatin-loaded poly(lactic-co-glycolic) acid (PLGA) NPs were obtained via ultrasonic emulsion solvent evaporation with PLGA as the carrier encapsulating pitavastatin. The effects and mechanism of pitavastatin-NPs on EPC proliferation in vitro were evaluated. Then, EPC that internalized pitavastatin-NPs were transplanted into rats after carotid artery injury. EPC homing, re-endothelialization, and neointima were evaluated by fluorescence labeling, evans Blue and hematoxylin/eosin (H&E) staining. Pitavastatin-NPs significantly improved EPC proliferation compared with control and pitavastatin group. Those effects were blocked by pretreatment with the pharmacological phosphoinositide 3-kinase (PI3K) blockers LY294002. After carotid artery injury, more transplanted EPC were detected in target zone in Pitavastatin-NPs group than pitavastatin and control group. Re-endothelialization was promoted and intimal hyperplasia was inhibited as well. Thus, pitavastatin-NPs promote EPC proliferation via PI3K signaling and accelerate recovery of injured carotid artery.

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      Most cited references 18

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      The phosphoinositide 3-kinase pathway.

       Lewis Cantley (2002)
      Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention.
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        Phosphoinositide kinases.

        Phosphatidylinositol, a component of eukaryotic cell membranes, is unique among phospholipids in that its head group can be phosphorylated at multiple free hydroxyls. Several phosphorylated derivatives of phosphatidylinositol, collectively termed phosphoinositides, have been identified in eukaryotic cells from yeast to mammals. Phosphoinositides are involved in the regulation of diverse cellular processes, including proliferation, survival, cytoskeletal organization, vesicle trafficking, glucose transport, and platelet function. The enzymes that phosphorylate phosphatidylinositol and its derivatives are termed phosphoinositide kinases. Recent advances have challenged previous hypotheses about the substrate selectivity of different phosphoinositide kinase families. Here we re-examine the pathways of phosphoinositide synthesis and the enzymes involved.
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          MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.

          MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression primarily through translational repression. In erythropoietic (E) culture of cord blood CD34+ progenitor cells, the level of miR 221 and 222 is gradually and sharply down-modulated. Hypothetically, this decline could promote erythropoiesis by unblocking expression of key functional proteins. Indeed, (i) bioinformatic analysis suggested that miR 221 and 222 target the 3' UTR of kit mRNA; (ii) the luciferase assay confirmed that both miRs directly interact with the kit mRNA target site; and (iii) in E culture undergoing exponential cell growth, miR down-modulation is inversely related to increasing kit protein expression, whereas the kit mRNA level is relatively stable. Functional studies show that treatment of CD34+ progenitors with miR 221 and 222, via oligonucleotide transfection or lentiviral vector infection, causes impaired proliferation and accelerated differentiation of E cells, coupled with down-modulation of kit protein: this phenomenon, observed in E culture releasing endogenous kit ligand, is magnified in E culture supplemented with kit ligand. Furthermore, transplantation experiments in NOD-SCID mice reveal that miR 221 and 222 treatment of CD34+ cells impairs their engraftment capacity and stem cell activity. Finally, miR 221 and 222 gene transfer impairs proliferation of the kit+ TF-1 erythroleukemic cell line. Altogether, our studies indicate that the decline of miR 221 and 222 during exponential E growth unblocks kit protein production at mRNA level, thus leading to expansion of early erythroblasts. Furthermore, the results on kit+ erythroleukemic cells suggest a potential role of these miRs in cancer therapy.
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            Author and article information

            Affiliations
            [1 ]Institution of Cardiovascular Research, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037 China
            [2 ]Cardiovascular Department, First People’s Hospital of Chong Qing Liang Jiang New Zone, Chongqing, 401120 China
            [3 ]GRID grid.470927.f, Cardiovascular Department, , The 180th Hospital of PLA, Quanzhou, ; Fujian, 362000 China
            Contributors
            doctorzhaoxiaohui@yahoo.com
            Journal
            Sci Rep
            Sci Rep
            Scientific Reports
            Nature Publishing Group UK (London )
            2045-2322
            22 December 2017
            22 December 2017
            2017
            : 7
            29273744
            5741712
            18286
            10.1038/s41598-017-18286-x
            © The Author(s) 2017

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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