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H19 Induces Abdomin...
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Li, Daniel Y.Tech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
(author)
H19 Induces Abdominal Aortic Aneurysm Development and Progression
- Article/chapterEnglish2018
Publisher, publication year, extent ...
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LIPPINCOTT WILLIAMS & WILKINS,2018
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LIBRIS-ID:oai:DiVA.org:uu-368446
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-368446URI
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https://doi.org/10.1161/CIRCULATIONAHA.117.032184DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:139376313URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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.
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Busch, AlbertTech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
(author)
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Jin, HongKarolinska Institutet
(author)
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Chernogubova, EkaterinaKarolinska Institutet
(author)
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Pelisek, JaroslavTech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
(author)
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Karlsson, JoakimUniv Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
(author)
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Sennblad, BengtUppsala universitet,Molekylär evolution,Science for Life Laboratory, SciLifeLab(Swepub:uu)bengtsb
(author)
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Liu, ShengliangTech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
(author)
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Lao, Shen
(author)
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Hofmann, PatrickUniv Hosp Frankfurt, Inst Cardiovasc Regenerat, Frankfurt, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Frankfurt, Germany
(author)
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Baecklund, AlexandraKarolinska Institutet
(author)
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Eken, Suzanne M.Karolinska Institutet
(author)
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Roy, JoyKarolinska Institutet
(author)
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Eriksson, PerKarolinska Institutet
(author)
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Dacken, BrianExemplar Genet, Sioux Ctr, IA USA
(author)
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Ramanujam, DeepakTech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany
(author)
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Dueck, AnneTech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany
(author)
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Engelhardt, StefanTech Univ Munich, Inst Pharmacol & Toxicol, Munich, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich, Munich, Germany
(author)
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Boon, Reinier A.Univ Hosp Frankfurt, Inst Cardiovasc Regenerat, Frankfurt, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Rhein Main, Frankfurt, Germany
(author)
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Eckstein, Hans-HenningTech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
(author)
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Spin, Joshua M.Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA
(author)
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Tsao, Philip S.Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA
(author)
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Maegdefessel, LarsKarolinska Institutet
(author)
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Karolinska InstitutetTech Univ Munich, Dept Vasc & Endovasc Surg, Klinikum Rechts Isar, Munich, Germany
(creator_code:org_t)
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In:Circulation: LIPPINCOTT WILLIAMS & WILKINS138:15, s. 1551-15680009-73221524-4539
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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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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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- MEDICAL AND HEALTH SCIENCES
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Circulation
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Uppsala University
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Karolinska Institutet