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      Icariside II ameliorates endothelial dysfunction by regulating the MAPK pathway via miR-126/SPRED1 in diabetic human cavernous endothelial cells

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          The aim of the study was to investigate whether miR-126, a regulator of MAPK signaling via targeting sprouty-related EVH1 domain-containing protein 1 ( SPRED1) mRNA, is involved in the process by which icariside II (ICA II) ameliorates endothelial dysfunction in human cavernous endothelial cells (hCECs) exposed to a diabetic-like environment.

          Materials and methods

          Primary hCECs were isolated and divided into three groups, normal control, diabetes mellitus (DM), and DM treated with ICA II. The cell proliferation and migration abilities of the hCECs were examined. The expression levels of endothelial-related microRNAs and relative target mRNAs ( SPRED1, phosphoinositol-3 kinase regulatory subunit 2, and vascular cell adhesion molecule 1) of miR-126 were determined by real-time PCR. The protein expression of endothelial nitric oxide synthase, receptor for advanced glycation end products, and SPRED1, and MAPK signaling activities was determined by Western blot analysis. In addition, miR-126 agomir and antagomir were used for transfection into hCECs to further testify the association between miR-126 and its targeting mRNA SPRED1.


          hCECs induced with glucose plus advanced glycation end product-BSA showed a significant decrease in endothelial nitric oxide synthase, Ki-67, and miR-126 expression; a downregulated cell migration ability and an increased receptor for advanced glycation end products level. ICA II could partially reverse these changes. SPRED1 mRNA showed a contrary tendency with the miR-126-3p changes. The level of SPRED1 protein increased after the hCECs were induced with glucose plus advanced glycation end product-BSA, and ICA II could rescue its aberrant expression. In addition, the MAPK pathway was downregulated in the hCECs under diabetic conditions, and ICA II could partially enhance its signaling activities. miR-126 was obviously downregulated, and SPRED1 was accordingly upregulated after miR-126 antagomir transfection, while ICA II treatment could recover the expressions of both miR-126 and SPRED1. Moreover, the upregulation of miR-126 and the inhibition of SPRED1 were noticed in the diabetic hCECs by further transfection with miR-126 agomir.


          ICA II could ameliorate endothelial dysfunction by regulating the MAPK pathway via miR-126/SPRED1 in hCECs exposed to a diabetic-like environment, and ICA II might be a protective agent for endothelial function in diabetic ED.

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          Most cited references 20

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          miR-126 regulates angiogenic signaling and vascular integrity.

          Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.
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            Erectile dysfunction.

             Neal Lue (2000)
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              Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase.

              Nitric oxide generated by endothelial nitric oxide synthase (eNOS) plays an important role in maintaining cardiovascular homeostasis. Under various pathological conditions, abnormal expression of eNOS contributes to endothelial dysfunction and the development of cardiovascular diseases. A variety of pathological stimuli has been reported to decrease eNOS expression mainly through decreasing eNOS mRNA stability by regulating the binding of several cytosolic proteins to the cis-acting sequences within eNOS mRNA 3' untranslated regions. However, the detailed mechanisms remain elusive. Because microRNAs inhibit gene expression through binding to the 3' untranslated regions of their target mRNAs, microRNAs may be the important posttranscriptional modulators of eNOS expression. Here, we provided evidence that eNOS is a direct target of miR-155. Overexpression of miR-155 decreased, whereas inhibition of miR-155 increased, eNOS expression and NO production in human umbilical vein endothelial cells and acetylcholine-induced endothelium-dependent vasorelaxation in human internal mammary arteries. Inflammatory cytokines including tumor necrosis factor-α increased miR-155 expression. Inhibition of miR-155 reversed tumor necrosis factor-α-induced downregulation of eNOS expression and impairment of endothelium-dependent vasorelaxation. Moreover, we observed that simvastatin attenuated tumor necrosis factor-α-induced upregulation of miR-155 and ameliorated the effects of tumor necrosis factor-α on eNOS expression and endothelium-dependent vasodilation. Simvastatin decreased miR-155 expression through interfering mevalonate-geranylgeranyl-pyrophosphate-RhoA signaling pathway. These findings indicated that miR-155 is an essential regulator of eNOS expression and endothelium-dependent vasorelaxation. Inhibition of miR-155 may be a new therapeutic approach to improve endothelial dysfunction during the development of cardiovascular diseases.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                13 June 2018
                : 12
                : 1743-1751
                [1 ]Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People’s Republic of China
                [2 ]Andrology Center, Peking University First Hospital, Peking University, Beijing 100034, People’s Republic of China
                Author notes
                Correspondence: Ruili Guan, Andrology Center, Peking University First Hospital, Peking University, No 8 Xishiku Street, Xicheng District, Beijing 100034, People’s Republic of China, Tel +86 10 8322 8989, Fax +86 10 8322 2822, Email guanruili@ 123456bjmu.edu.cn
                Xiaodong Zhang, Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, No 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, People’s Republic of China, Tel/fax +86 10 8523 1247, Email zxdcyyy@ 123456163.com
                © 2018 Lei et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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