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  • Hamblin, Milton  (5)
  • 2010-2014  (5)
  • 1
    Online Resource
    Online Resource
    Abstract TP117: MiR-15a/16-1 Cluster Inhibits Angiogenesis In Mouse After Ischemic Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Angiogenesis may occur as a natural defense response against neurological diseases. Accumulating studies have shown that post-ischemic angiogenesis promotes functional recovery after ischemic stroke and is related to longer survival time in ischemic stroke patients. MicroRNAs (miRs) have been documented as a novel family of noncoding small RNAs that negatively modulate protein expression in various organisms. Recent studies have revealed important roles for miRs in regulating angiogenesis. However, the function of miRs in the angiogenic processes after ischemic stroke is unknown. We have previously demonstrated that the miR-15a/16-1 cluster has an anti-survival role in ischemia-induced endothelial cell death. Here we further investigate the role of the miR-15a/16-1 cluster in the regulation of post-ischemic angiogenesis. We have shown that expression of the miR-15a/16-1 cluster is significantly increased in the cerebral vasculature at the penumbral area 7 days after mouse middle cerebral artery occlusion (MCAO). Accordingly, in comparison with the wild-type animals, endothelial cell (EC)-selective miR-15a/16-1 transgenic overexpression leads to reduced cerebral blood vessel formation, increased brain infarction and neurological deficits in mice 7 days post-MCAO. Mechanistically, lentivirus-mediated miR-15a/16-1 gain- or loss-of-function reduces or increases FGFR1 and VEGF mRNA or protein levels in mouse cerebral vascular endothelial cell cultures, respectively. Through the bioinformatics analysis, 3’UTR luciferase reporter assays, and immunoassays, we further found that miR-15a and miR-16-1 bind to the 3’UTR of FGFR1 or VEGF mRNA, and directly inhibit FGFR1 and VEGF activities. Our findings suggest the miR-15a/16-1 cluster can suppress post-ischemic cerebral angiogenesis through direct inhibition of endothelial FGFR1 and VEGF activities. Elucidating the molecular mechanism of miR-15a/16-1 cluster-mediated angiogenesis will provide new insights into the understanding of miR function in the post-ischemic neurovascular remodeling and neurological recovery and open a new area with potential promise for further development of neurorestorative therapies after ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.ATP117
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor
    Oxford University Press (OUP) ; 2011
    In:  Cardiovascular Research Vol. 91, No. 1 ( 2011-7-1), p. 90-98
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 91, No. 1 ( 2011-7-1), p. 90-98
    Type of Medium: Online Resource
    ISSN: 1755-3245 , 0008-6363
    URL: Article
    DOI: 10.1093/cvr/cvr068
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2011
    detail.hit.zdb_id: 1499917-1
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  • 3
    Online Resource
    Online Resource
    KLF11 mediates PPARγ cerebrovascular protection in ischaemic stroke
    Oxford University Press (OUP) ; 2013
    In:  Brain Vol. 136, No. 4 ( 2013-4), p. 1274-1287
    Details
    In: Brain, Oxford University Press (OUP), Vol. 136, No. 4 ( 2013-4), p. 1274-1287
    Type of Medium: Online Resource
    ISSN: 1460-2156 , 0006-8950
    URL: Article
    DOI: 10.1093/brain/awt002
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2013
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Nitro-Oleic Acid Inhibits Angiotensin II–Induced Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Circulation Research Vol. 107, No. 4 ( 2010-08-20), p. 540-548
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 4 ( 2010-08-20), p. 540-548
    Abstract: Nitro-oleic acid (OA-NO 2 ) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO 2 exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature. Objective: The present study sought to investigate the protective role of OA-NO 2 in angiotensin (Ang) II–induced hypertension. Methods and Results: We show that systemic administration of OA-NO 2 results in a sustained reduction of Ang II–induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO 2 significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT 1 R)-mediated signaling because vascular contraction by other G-protein–coupled receptors is not altered in response to OA-NO 2 treatment. From the mechanistic viewpoint, OA-NO 2 lowers Ang II–induced hypertension independently of peroxisome proliferation-activated receptor (PPAR)γ activation. Rather, OA-NO 2 , but not OA, specifically binds to the AT 1 R, reduces heterotrimeric G-protein coupling, and inhibits IP 3 (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor. Conclusions: These results demonstrate that OA-NO 2 diminishes the pressor response to Ang II and inhibits AT 1 R-dependent vasoconstriction, revealing OA-NO 2 as a novel antagonist of Ang II–induced hypertension.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.110.218404
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 1467838-X
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  • 5
    Online Resource
    Online Resource
    Abstract W P362: Krupple-Like Factor 11 Mediates Blood-Brain Barrier Dysfunction in Ischemic Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. suppl_1 ( 2014-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. suppl_1 ( 2014-02)
    Abstract: The blood-brain barrier (BBB) is one of the primary targets of cerebral ischemic insults. Extensive studies have shown that breakdown of BBB integrity initiates a devastating cascade of events and eventual neuronal loss in cerebral ischemia. Thus, it is important to identify mechanisms by which loss of BBB integrity can be reduced under ischemic stroke conditions. Kruppel-like factors (KLF) are members of the zinc finger family of transcription factors and play key roles in cellular growth and differentiation. Up to now, the function of the KLF family in the cerebral vasculature is largely unexplored. KLF11 is a member of the KLF family with high expression in vascular endothelium. Mutations or variations in KLF11 gene are closely associated with human type 2 diabetes mellitus, a major risk factor for stroke. Previously, we have demonstrated that peroxisome proliferator-activated receptor γ-mediated cerebral vascular protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. However, the functional significance and mechanisms of KLF11 itself in regulating cerebrovascular pathogenesis are totally unknown in ischemic stroke. Here we have shown that KLF11 expression is significantly decreased in the cerebral vasculature, cerebral cortex, and cultured BMECs after in vivo and in vitro ischemic stimuli. KLF11 genetic deficiency leads to increased BBB permeability in mouse brain after middle cerebral artery occlusion as well as increased leukocyte-endothelial rolling and adhesion in the vascular wall. Moreover, we also demonstrated that gain-of-KLF11 function by adenovirus can significantly inhibit BMEC death after exposure to Oxygen Glucose Deprivation. Mechanistically, we found several potential KLF11 binding sites in the promoter region of selective endothelial tight junctions. Genetic deletion of KLF11 in mice significantly reduced cerebral expression of Claudin 5 and ZO-1 mRNAs. These findings suggest that KLF11 functions as a novel master regulator in BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of KLF11-mediated BBB protection may lead us to discover novel pharmaceutical targets for the development of effective therapies against ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.45.suppl_1.wp362
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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