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H19 Induces Abdomin...
H19 Induces Abdominal Aortic Aneurysm Development and Progression
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- Li, Daniel Y. (author)
- Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
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- Busch, Albert (author)
- Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
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- Jin, Hong (author)
- Karolinska Institutet
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- Chernogubova, Ekaterina (author)
- Karolinska Institutet
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- Pelisek, Jaroslav (author)
- Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
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- Karlsson, Joakim (author)
- Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
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- Sennblad, Bengt (author)
- Uppsala universitet,Molekylär evolution,Science for Life Laboratory, SciLifeLab
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- Liu, Shengliang (author)
- Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
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Lao, Shen (author)
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- Hofmann, Patrick (author)
- Univ Hosp Frankfurt, Inst Cardiovasc Regenerat, Frankfurt, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Frankfurt, Germany
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- Baecklund, Alexandra (author)
- Karolinska Institutet
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- Eken, Suzanne M. (author)
- Karolinska Institutet
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- Roy, Joy (author)
- Karolinska Institutet
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- Eriksson, Per (author)
- Karolinska Institutet
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- Dacken, Brian (author)
- Exemplar Genet, Sioux Ctr, IA USA
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- Ramanujam, Deepak (author)
- Tech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany
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- Dueck, Anne (author)
- Tech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany
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- Engelhardt, Stefan (author)
- Tech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany
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- Boon, Reinier A. (author)
- Univ Hosp Frankfurt, Inst Cardiovasc Regenerat, Frankfurt, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Frankfurt, Germany
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- Eckstein, Hans-Henning (author)
- Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
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- Spin, Joshua M. (author)
- Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA
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- Tsao, Philip S. (author)
- Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA
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- Maegdefessel, Lars (author)
- Karolinska Institutet
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(creator_code:org_t)
- LIPPINCOTT WILLIAMS & WILKINS, 2018
- 2018
- English.
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 138:15, s. 1551-1568
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- abdominal aortic aneurysm
- long noncoding RNA
- molecular medicine
- smooth muscle cells
- translations
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Li, Daniel Y.
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Busch, Albert
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Jin, Hong
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Chernogubova, Ek ...
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Pelisek, Jarosla ...
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Karlsson, Joakim
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show more...
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Sennblad, Bengt
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Liu, Shengliang
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Lao, Shen
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Hofmann, Patrick
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Baecklund, Alexa ...
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Eken, Suzanne M.
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Roy, Joy
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Eriksson, Per
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Dacken, Brian
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Ramanujam, Deepa ...
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Dueck, Anne
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Engelhardt, Stef ...
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Boon, Reinier A.
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Eckstein, Hans-H ...
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Spin, Joshua M.
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Tsao, Philip S.
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Maegdefessel, La ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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Circulation
- By the university
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Uppsala University
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Karolinska Institutet