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About hyaluronan in the hypertrophic heart: studies on coordinated regulation of extracellular matrix signalling
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Myocardial hypertrophy is a risk factor for cardiovascular morbidity and mortality. Independent of underlying disease, the cardiac muscle strives in different ways to compensate for an increased workload. This remodelling of the heart includes changes in the extracellular matrix which will affect systolic and diastolic cardiac function. Furthermore, signal transduction, molecular diffusion and microcirculation will be affected in the hypertrophic process. One important extracellular component is the glycosaminoglycan hyaluronan. It has been shown to play a major role in other conditions that feature cellular growth and proliferation, such as wound healing and malignancies. The aim of this thesis was to investigate hyaluronan and its role in both an experimental rat model of cardiac hypertrophy as well as in cultured mouse cardiomyocytes and fibroblasts.

Methods. Cardiac hypertrophy was induced in rats by aortic ligation. Hyaluronan concentration was measured and expression of genes coding for hyaluronan synthases were quantified after 1, 6 and 42 days after operation, in cardiac tissue from the left ventricular wall. Localization of hyaluronan and its receptor CD44 was studied histochemically. Hyaluronan synthesis was correlated to gene transcription using microarray gene expression analysis. Cultures of cardiomyocytes and fibroblasts were stimulated with growth factors. Hyaluronan concentration was measured and expression of genes coding for hyaluronan synthases were detected. Hyaluronan size was measured and crosstalk between cardiomyocytes and fibroblasts was investigated.

Results. Increased concentration of hyaluronan in hypertrophied cardiac tissue was observed together with an up-regulation of two hyaluronan synthase genes. Hyaluronan was detected in the myocardium and in the adventitia of cardiac arteries whereas CD44 staining was mainly found in and around the adventitia. Hyaluronan synthesis correlated to the expression of genes, regulated by transcription factors known to initiate cardiac hypertrophy. Stimulation of cardiomyocytes by PDGF-BB induced synthesis of hyaluronan. Cardiomyocytes also secreted a factor into culture media that after transfer to fibroblasts initiated an increased synthesis of hyaluronan. When stimulated with hyaluronan of different sizes, a change in cardiomyocyte gene expression was observed. Different growth factors induced production of different sizes of hyaluronan in fibroblasts. The main synthase detected was hyaluronan synthase-2. Cardiomyocytes were also shown to secrete microvesicles containing both DNA and RNA. Isolated microvesicles incubated with fibroblasts were observed by confocal microscopy to be internalized into fibroblasts. Altered gene expression was observed in microvesicle stimulated fibroblasts.

Conclusion. This study shows that increased hyaluronan synthesis in cardiac tissue during hypertrophic development is a part of the extracellular matrix remodelling. Cell cultures revealed the ability of cardiomyocytes to both synthesize hyaluronan and to convey signals to fibroblasts, causing them to increase hyaluronan synthesis. Cardiomyocytes are likely to express receptors for hyaluronan, which mediate intracellular signalling causing the observed altered gene expression in cardiomyocytes stimulated with hyaluronan. This demonstrates the extensive involvement of hyaluronan in cardiac hypertrophy.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2010. , 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1359
Keyword [en]
hyaluronan, hyaluronan synthases, gene expression, extracellular matrix, cardiac hypertrophy, rat (wistar, male), cardiomyocytes, growth factors, fibroblasts, microvesicles, exosomes
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-35491ISBN: 978-91-7459-043-2 (print)OAI: oai:DiVA.org:umu-35491DiVA: diva2:344730
Public defence
2010-09-10, Sal B, 9 trappor, byggnad 1 b, NUS, Umeå, 13:04 (Swedish)
Opponent
Supervisors
Available from: 2010-08-26 Created: 2010-08-20 Last updated: 2010-08-26Bibliographically approved
List of papers
1. Parallel up-regulation of FGF-2 and hyaluronan during development of cardiac hypertrophy in rat
Open this publication in new window or tab >>Parallel up-regulation of FGF-2 and hyaluronan during development of cardiac hypertrophy in rat
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2008 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 332, no 1, 49-56 p.Article in journal (Refereed) Published
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-8347 (URN)10.1007/s00441-007-0562-8 (DOI)18196276 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-14Bibliographically approved
2. Temporal correlation between transcriptional changes and increased synthesis of hyaluronan in experimental cardiac hypertrophy
Open this publication in new window or tab >>Temporal correlation between transcriptional changes and increased synthesis of hyaluronan in experimental cardiac hypertrophy
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2010 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 96, no 2, 73-81 p.Article in journal (Refereed) Published
Abstract [en]

The role of hyaluronan in cardiac growth has become evident, previously shown by increased myocardial levels of hyaluronan in a rat model of cardiac hypertrophy. To further investigate the role of hyaluronan and regulation of its synthesis in cardiac hypertrophy, quantitative measurements of myocardial hyaluronan concentration was correlated to gene transcription in hypertrophic cardiac tissue. Factor analysis was used to study this correlation over time. A subset of differentially expressed genes was identified with a transcriptional regulation correlating to the increased synthesis of hyaluronan, suggesting a common regulatory pathway. Four transcription factors, Myc, Fos, Junb and Egr1, were also up-regulated. Furthermore, the Ace gene was up-regulated, representing increase of angiotensin II, an inducer of these transcription factors and fetal genes in cardiac hypertrophy. This demonstrates a coordinated synthesis of hyaluronan and pro-hypertrophic gene expression, regulated by immediate early genes, with angiotensin II as a possible mediator.

Keyword
Cardiac hypertrophy, gene expression, hyaluronan, Extracellular matrix, Remodeling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-35230 (URN)10.1016/j.ygeno.2010.04.003 (DOI)000280443800002 ()20417270 (PubMedID)
Available from: 2010-08-10 Created: 2010-08-10 Last updated: 2017-12-12Bibliographically approved
3. Hyaluronan is both a product and stimulator of cardiomyocytes: a study in cell cultures of cardiomyocytes and fibroblasts
Open this publication in new window or tab >>Hyaluronan is both a product and stimulator of cardiomyocytes: a study in cell cultures of cardiomyocytes and fibroblasts
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(English)Article in journal (Refereed) Submitted
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-35489 (URN)
Available from: 2010-08-20 Created: 2010-08-20 Last updated: 2016-01-22
4. Cardiomyocyte microvesicles convey bioinformatic messages to target cells
Open this publication in new window or tab >>Cardiomyocyte microvesicles convey bioinformatic messages to target cells
(English)Article in journal (Refereed) Submitted
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-35490 (URN)
Available from: 2010-08-20 Created: 2010-08-20 Last updated: 2016-01-22

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