Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2010

Open Access 01-12-2010 | Research

"Hypoxia-induced down-regulation of microRNA-449a/b impairs control over targeted SERPINE1 (PAI-1) mRNA - a mechanism involved in SERPINE1 (PAI-1) overexpression"

Authors: Michaela Muth, Katharina Theophile, Kais Hussein, Christoph Jacobi, Hans Kreipe, Oliver Bock

Published in: Journal of Translational Medicine | Issue 1/2010

Login to get access

Abstract

Background

In damaged organs tissue repair and replacement of cells by connective tissue provokes a response of fibroblasts to cellular stress factors such as hypoxia.
MicroRNAs (miRNA) are small non-coding RNA molecules which bind to their mRNA targets which eventually lead to repression of translation. Whether the response of fibroblasts to stress factors also involves the miRNA system is largely unknown.

Results

By miRNA profiling we identified down-regulation of miRNA-449a/b expression in hypoxic fibroblasts. Specific miRNA inhibitors and mimics showed direct evidence for targeting the serine protease inhibitor (serpin) protein (SERPINE1; plasminogen activator inhibitor-1, PAI-1) by miRNA-449a/b leading to SERPINE1 mRNA and protein up- and down-regulation, respectively. SERPINE1 expression in vivo could be located predominantly in areas of fibrosis and remodeling.

Conclusions

Our study offers serious lines of evidence for a novel hypoxia-dependent mechanism involving hypoxia-induced decrease of clustered miRNA-449a/b, hypoxia-induced amplification of concomitant increase of targeted SERPINE1 (PAI-1) and its overexpression in tissues showing a hypoxic environment.
Appendix
Available only for authorised users
Literature
1.
2.
Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, Kim KJ, Park BS, Sung JH: Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF andbFGF. Wound Repair Regen. 2009, 17 (4): 540-7. 10.1111/j.1524-475X.2009.00499.x.PubMedCrossRef
3.
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002, 3 (5): 349-63. 10.1038/nrm809.PubMedCrossRef
4.
5.
Hopkins DR, Keles S, Greenspan DS: The bone morphogenetic protein 1/Tolloid-like metalloproteinases. Matrix Biol. 2007, 26 (7): 508-23. 10.1016/j.matbio.2007.05.004.PubMedPubMedCentralCrossRef
6.
Emmert-Buck MR, Roth MJ, Zhuang Z, Campo E, Rozhin J, Sloane BF, Liotta LA: Stetler-Stevenson WG Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples. Am J Pathol. 1994, 145 (6): 1285-90.PubMedPubMedCentral
7.
Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, andbiochemistry. Circ Res. 2003, 92 (8): 827-39. 10.1161/01.RES.0000070112.80711.3D.PubMedCrossRef
8.
Wang H, Zhang Y, Heuckeroth RO: PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. FEBS Lett. 2007, 581 (16): 3098-104. 10.1016/j.febslet.2007.05.049.PubMedCrossRef
9.
Gaertner R, Jacob MP, Prunier F, Angles-Cano E, Mercadier JJ, Michel JB: The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat. J Mol Cell Cardiol. 2005, 38 (1): 193-204. 10.1016/j.yjmcc.2004.10.017.PubMedCrossRef
10.
Laiho M, Saksela O, Keski-Oja J: Transforming growth factor-beta induction of type-1 plasminogen activator inhibitor. Pericellular deposition and sensitivity to exogenous urokinase. J Biol Chem. 1987, 262 (36): 17467-74.PubMed
11.
Wilkins-Port CE, Ye Q, Mazurkiewicz JE, Higgins PJ: TGF-beta1 + EGF-initiated invasive potential in transformed human keratinocytes is coupled to a plasmin/MMP-10/MMP-1-dependent collagen remodeling axis: role forPAI-1. Cancer Res. 2009, 69 (9): 4081-91. 10.1158/0008-5472.CAN-09-0043.PubMedPubMedCentralCrossRef
12.
13.
Hobert O: Gene regulation by transcription factors andmicroRNAs. Science. 2008, 319: 1785-1786. 10.1126/science.1151651.PubMedCrossRef
14.
Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S: MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling infibroblasts. Nature. 2008, 456 (7224): 980-4. 10.1038/nature07511.PubMedCrossRef
15.
Schönermark MP, Bock O, Büchner A, Steinmeier R, Benbow U, Lenarz T: Quantification of tumor cell invasion using confocal laser scan microscopy. Nat Med. 1997, 3 (10): 1167-71. 10.1038/nm1097-1167.PubMedCrossRef
16.
Mamori S, Asakura T, Ohkawa K, Tajiri H: Survivin expression in early hepatocellular carcinoma and post-treatment with anti-cancer drug under hypoxic culture condition. World J Gastroenterol. 2007, 13 (40): 5306-11.PubMedPubMedCentralCrossRef
17.
Kamiya T, Kwon AH, Kanemaki T, Matsui T, Uetsuji S, Okumura T, Kamiyama Y: A simplified model of hypoxic injury in primary cultured rat hepatocytes, In Vitro. Cell Dev Biol Anim. 1998, 34: 131-137. 10.1007/s11626-998-0095-9.CrossRef
18.
Bock O, Kreipe H, Lehmann U: One-Step Extraction of RNA from Archival Biopsies. Anal Biochem. 2001, 295: 116-117. 10.1006/abio.2001.5188.PubMedCrossRef
19.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT Method. Methods. 2001, 25: 402-8. 10.1006/meth.2001.1262.PubMedCrossRef
20.
21.
Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS: Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl AcadSci USA. 1986, 83 (12): 4167-71. 10.1073/pnas.83.12.4167.CrossRef
22.
Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, Calin GA, Ivan M: A microRNA signature of hypoxia. Mol Cell Biol. 2007, 27 (5): 1859-67. 10.1128/MCB.01395-06.PubMedPubMedCentralCrossRef
23.
Guimbellot JS, Erickson SW, Mehta T, Wen H, Page GP, Sorscher EJ, Hong JS: Correlation of microRNA levels during hypoxia with predicted target mRNAs through genome-wide microarray analysis. BMC Med Genomics. 2009, 2: 15-10.1186/1755-8794-2-15.PubMedPubMedCentralCrossRef
24.
Bock O, Muth M, Theophile K, Winter M, Hussein K, Büsche G, Kröger N, Kreipe H: Identification of new target molecules PTK2, TGFBR2 and CD9 overexpressed during advanced bone marrow remodelling in primary myelofibrosis. Br J Haematol. 2009, 146 (5): 510-20. 10.1111/j.1365-2141.2009.07808.x.PubMedCrossRef
25.
Redshaw N, Wheeler G, Hajihosseini MK, Dalmay T: microRNA-449 is a putative regulator of choroid plexus development and function. Brain Res. 2009, 1250: 20-6. 10.1016/j.brainres.2008.11.020.PubMedCrossRef
26.
Greco S, De Simone M, Colussi C, Zaccagnini G, Fasanaro P, Pescatori M, Cardani R, Perbellini R, Isaia E, Sale P, Meola G, Capogrossi MC, Gaetano C, Martelli F: Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia. FASEB J. 2009, 23 (10): 3335-46. 10.1096/fj.08-128579.PubMedCrossRef
27.
Xu Y, Hagege J, Mougenot B, Sraer JD, Rønne E, Rondeau E: Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney. Kidney Int. 1996, 50 (6): 2011-9. 10.1038/ki.1996.523.PubMedCrossRef
28.
Pontrelli P, Ranieri E, Ursi M, Ghosh-Choudhury G, Gesualdo L, Paolo Schena F, Grandaliano G: jun-N-terminal kinase regulates thrombin-induced PAI-1 gene expression in proximal tubular epithelial cells. Kidney Int. 2004, 65 (6): 2249-61. 10.1111/j.1523-1755.2004.00644.x.PubMedCrossRef
29.
Ha H, Oh EY, Lee HB: The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases. Nat Rev Nephrol. 2009, 5 (4): 203-11. 10.1038/nrneph.2009.15.PubMedCrossRef
30.
Watson JA, Watson CJ, McCrohan AM, Woodfine K, Tosetto M, McDaid J, Gallagher E, Betts D, Baugh J, O'Sullivan J, Murrell A, Watson RW, McCann A: Generation of an epigenetic signature by chronic hypoxia in prostate cells. Hum Mol Genet. 2009, 18 (19): 3594-604. 10.1093/hmg/ddp307.PubMedCrossRef
31.
Lyons RM, Gentry LE, Purchio AF, Moses HL: Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol. 1990, 110 (4): 1361-7. 10.1083/jcb.110.4.1361.PubMedCrossRef
32.
Sakamoto T, Woodcock-Mitchell J, Marutsuka K, Mitchell JJ, Sobel BE, Fujii S: TNF-alpha and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes. Am J Physiol. 1999, 276: C1391-7.PubMed
33.
Doller A, Gauer S, Sobkowiak E, Geiger H, Pfeilschifter J, Eberhardt W: Angiotensin II induces renal plasminogen activator inhibitor-1 and cyclooxygenase-2 expression post-transcriptionally via activation of the mRNA-stabilizing factor human-antigen R. Am J Pathol. 2009, 174 (4): 1252-63. 10.2353/ajpath.2009.080652.PubMedPubMedCentralCrossRef
34.
Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M: Banff 07 classification of renal allograft pathology: updates and futuredirections. Am J Transplant. 2008, 8 (4): 753-60. 10.1111/j.1600-6143.2008.02159.x.PubMedCrossRef
Metadata
Title
"Hypoxia-induced down-regulation of microRNA-449a/b impairs control over targeted SERPINE1 (PAI-1) mRNA - a mechanism involved in SERPINE1 (PAI-1) overexpression"
Authors
Michaela Muth
Katharina Theophile
Kais Hussein
Christoph Jacobi
Hans Kreipe
Oliver Bock
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2010
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-8-33

Other articles of this Issue 1/2010

Journal of Translational Medicine 1/2010 Go to the issue

Research

Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features

Review

Biomedical informatics and translational medicine

Research

Ezrin promotes invasion and metastasis of pancreatic cancer cells

Research

Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies

Commentary

Strategy Escalation: An emerging paradigm for safe clinical development of T cell gene therapies

Research

Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits