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- Li, D. Y., et al.
(författare)
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H19 Induces Abdominal Aortic Aneurysm Development and Progression
- 2018
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 138:15, s. 1551-1568
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1 as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1 and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1 via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
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- Maegdefessel, L, et al.
(författare)
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miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development
- 2014
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 5214-
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Tidskriftsartikel (refereegranskat)abstract
- Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
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| 9. |
- Nanda, V, et al.
(författare)
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Membership spotlight
- 2015
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Ingår i: Vascular medicine (London, England). - 1477-0377. ; 20:3, s. 274-274
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Oliveira, G. J. P. L., et al.
(författare)
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Effect of avocado/soybean unsaponifiables on ligature-induced bone loss and bone repair after ligature removal in rats
- 2016
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Ingår i: Journal of Periodontal Research. - : Wiley-Blackwell Publishing Inc.. - 0022-3484 .- 1600-0765. ; 51:3, s. 332-341
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveThe aim of this study was to evaluate the effects of administration of avocado/soybean unsaponifiable (ASU), a drug that is commonly used in the treatment of rheumatoid arthritis, on ligature-induced bone loss and bone repair after ligature removal in rats. Material and MethodsEighty-four rats were randomly assigned to four groups of equal size and received a daily gavageof either sterile saline [control (CTR)] or ASU (0.6mg/kg), starting 7d before (ASU/-7), on the day of (ASU/0) or 7d after (ASU/+7) periodontitis induction. Periodontitis was induced by placing silk ligatures into the gingival sulcus of the second maxillary molars for 7d; after 7d, the ligatures were removed. Seven rats from each group were sacrificed, 7, 15 or 30d after ligature removal. Bone resorption was evaluated by histomorphometry and micro-computed tomography (micro-CT). Immunohistochemistry was used to evaluate the expression of TRAP, RANKL and alkaline phosphatase (ALP), and quantitative PCR (qPCR) was used to evaluate the levels of interleukin-1beta (Il1), tumor necrosis factor alpha (Tnf), interleukin-6 (Il-6), Rankl and Alp. Statistical analysis was performed using the Shapiro-Wilk test, ANOVA and Tukey's test for normal data, and using the Kruskall-Wallis and Dunnet's tests for non-normal data (p<0.05 ResultsHistomorphometry and micro-CT analysis showed greater bone resorption in the CTR group than in the ASU/0 (15d) and ASU/+7 (7 and 15d) groups. The CTR group also presented with a higher expression of TRAP (15 and 30d) and RANKL (7 and 15d) compared with ASU/0 and ASU/+7 groups. Similarly, qPCR analysis showed higher levels of Rankl and Il1 mRNAs, and lower levels of Alp mRNA, in the CTR group compared with all other groups (for all periods ConclusionASU exhibited a positive effect on bone repair following ligature-induced periodontitis in rats
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