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  1. Article: Role of microRNAs in vascular diseases, inflammation, and angiogenesis.

    Urbich, Carmen / Kuehbacher, Angelika / Dimmeler, Stefanie

    Cardiovascular research

    2008  Volume 79, Issue 4, Page(s) 581–588

    Abstract: The integrity of the endothelial monolayer is fundamental for the homoeostasis of the vascular system. Functional endothelial cells are also required for the growth of new blood vessels during neovascularization. Although multiple growth factors have ... ...

    Abstract The integrity of the endothelial monolayer is fundamental for the homoeostasis of the vascular system. Functional endothelial cells are also required for the growth of new blood vessels during neovascularization. Although multiple growth factors have been shown to regulate angiogenesis and vascular development, little is known about the complex upstream regulation of gene expression and translation. MicroRNAs (miRNAs) are an emerging class of highly conserved, non-coding small RNAs that regulate gene expression on the post-transcriptional level by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA. More than 500 human miRNAs have been identified so far, and increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in various physiological and pathological processes such as cardiogenesis, haematopoietic lineage differentiation, and oncogenesis. Meanwhile, a few specific miRNAs that regulate endothelial cell functions and angiogenesis have been described. Let7-f, miR-27b, and mir-130a were identified as pro-angiogenic miRNAs. In contrast, miR-221 and miR-222 inhibit endothelial cell migration, proliferation, and angiogenesis in vitro by targeting the stem cell factor receptor c-kit and indirectly regulating endothelial nitric oxide synthase expression. Moreover, some miRNAs are involved in tumour angiogenesis such as the miR-17-92 cluster and miR-378. Early studies also indicate the contribution of specific miRNAs (e.g. miR-155, miR-21, and miR-126) to vascular inflammation and diseases. Thus, the identification of miRNAs and their respective targets may offer new therapeutic strategies to treat vascular diseases such as atherosclerosis, to improve neovascularization after ischaemia, or to prevent tumour progression.
    MeSH term(s) Animals ; Endothelium, Vascular/enzymology ; Endothelium, Vascular/metabolism ; Gene Expression Regulation ; Genetic Therapy ; Humans ; Inflammation/genetics ; Inflammation/physiopathology ; Inflammation/therapy ; MicroRNAs/metabolism ; Neovascularization, Physiologic/genetics ; RNA Processing, Post-Transcriptional ; Ribonuclease III/metabolism ; Vascular Diseases/genetics ; Vascular Diseases/physiopathology ; Vascular Diseases/therapy
    Chemical Substances MicroRNAs ; DROSHA protein, human (EC 3.1.26.3) ; Drosha protein, mouse (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3)
    Language English
    Publishing date 2008-09-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1093/cvr/cvn156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Targeting microRNA expression to regulate angiogenesis.

    Kuehbacher, Angelika / Urbich, Carmen / Dimmeler, Stefanie

    Trends in pharmacological sciences

    2008  Volume 29, Issue 1, Page(s) 12–15

    Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. More than 400 miRNAs have been identified in the human genome, but the ... ...

    Abstract MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. More than 400 miRNAs have been identified in the human genome, but the relevance of most of them to physiological and pathological processes remains unclear. Although downregulation of the miRNA-processing enzymes Dicer and Drosha is known to impair angiogenesis, only a few specific miRNAs targeting endothelial cell function and angiogenesis have been identified. miR-221 and miR-222 block endothelial cell migration, proliferation and angiogenesis in vitro by targeting the stem cell factor receptor c-Kit and indirectly regulating expression of endothelial nitric oxide synthase. A pro-angiogenic function has been established for the miR-17-92 cluster, which promotes tumor angiogenesis in vivo. Expression of let7-f and miR-27b contributes to in vitro angiogenesis. We review recent studies on the involvement of miRNA in angiogenesis and discuss their implications for miRNA-based therapeutic strategies targeting this process in disease.
    MeSH term(s) Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/physiopathology ; Drug Delivery Systems ; Gene Expression Regulation/drug effects ; Humans ; MicroRNAs/drug effects ; MicroRNAs/metabolism ; Neoplasms/drug therapy ; Neoplasms/physiopathology ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/physiopathology ; Neovascularization, Physiologic/physiology
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2008-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2007.10.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis.

    Kuehbacher, Angelika / Urbich, Carmen / Zeiher, Andreas M / Dimmeler, Stefanie

    Circulation research

    2007  Volume 101, Issue 1, Page(s) 59–68

    Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to the cellular transcript leading to translational repression or degradation of the target mRNA. Dicer and Drosha are the miRNA processing enzymes that are required for ...

    Abstract MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to the cellular transcript leading to translational repression or degradation of the target mRNA. Dicer and Drosha are the miRNA processing enzymes that are required for the maturation of miRNAs. Here, we investigated the role of Dicer and Drosha for angiogenesis. Endothelial cells were transfected with siRNA against Dicer and Drosha to inhibit miRNA biogenesis. Genetic silencing of Dicer and Drosha significantly reduced capillary sprouting of endothelial cells and tube forming activity. Migration of endothelial cells was significantly decreased in Dicer siRNA-transfected cells, whereas Drosha siRNA had no effect. Silencing of Dicer but not of Drosha reduced angiogenesis in vivo. Next, we attempted to identify miRNAs expressed in endothelial cells. A screening analysis of 168 human miRNAs using real-time PCR revealed that members of the let-7 family, mir-21, mir-126, mir-221, and mir-222 are highly expressed in endothelial cells. Dicer and Drosha siRNA reduced lef-7f and mir-27b expression. Inhibitors against let-7f and mir-27b also reduced sprout formation indicating that let-7f and mir-27b promote angiogenesis by targeting antiangiogenic genes. In silico analysis of predicted targets for let-7 cluster identified the endogenous angiogenesis inhibitor thrombospondin-1. Indeed, Dicer and Drosha siRNA significantly increased the expression of thrombospondin-1. Taken together, transient reduction of the miRNA-regulating enzyme Dicer impairs angiogenesis in vitro and in vivo, whereas Drosha siRNA induced a minor antiangiogenic effect in vitro and was not effective in vivo. The let-7 family and mir-27b appear to be attractive targets for modulating angiogenesis.
    MeSH term(s) Cell Movement/genetics ; Cells, Cultured ; Endothelial Cells/metabolism ; Endothelial Cells/physiology ; Gene Expression Regulation/physiology ; Humans ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; Neovascularization, Physiologic/genetics ; Ribonuclease III/physiology
    Chemical Substances MicroRNAs ; DROSHA protein, human (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3)
    Language English
    Publishing date 2007-07-06
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.107.153916
    Database MEDical Literature Analysis and Retrieval System OnLINE

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