Analysis of altered gene expression during sustained atrial fibrillation in the goat

Victor L J L Thijssen, Huub M W van der Velden, Erwin P van Ankeren, Jannie Ausma, Maurits A Allessie, Marcel Borgers, Guillaume J J M van Eys, Habo J Jongsma

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECTIVE: Atrial fibrillation (AF) is characterised by electrical, gap junctional and structural remodelling. However, the underlying molecular mechanisms of these phenomena are largely unknown. To get more insight into atrial remodelling at the molecular level we have analysed changes in gene expression during sustained AF in the goat.

METHODS: The differential display technique (DD) was used to identify genes differentially expressed during sustained AF (13.9 +/- 5.2 weeks) as compared to sinus rhythm (SR). Dot-blot analysis was performed to confirm the altered gene expression and to establish the changes in expression after 1, 2, 4, 8 and 16 weeks of AF. Immunohistochemistry and western blotting were used to validate the DD approach and to further characterise the changed expression of the beta-myosin heavy chain gene at the protein level.

RESULTS: Of the approximately 125 fragments that showed changed expression levels during AF, 34 were cloned and sequenced. Twenty-one of these represented known genes involved in cardiomyocyte structure, metabolism, expression regulation, or differentiation status. The changed expression of 70% of the isolated clones could be confirmed by dot-blot analysis. In addition, time course analysis revealed different profiles of expression as well as transient re-expression of genes, e.g. the gene for hypoxia-inducible factor 1 alpha during the first week of AF. During sustained AF the frequency of cardiomyocytes expressing beta myosin heavy chain (beta MHC) increased from 21.8 +/- 2.1 to 47.9 +/- 2.5% (S.E.M.). The overall expression of MHC (alpha+beta) appeared to be down-regulated during AF.

CONCLUSIONS: AF is accompanied by changes in expression of proteins involved in cellular structure, metabolism, gene expression regulation and (de-)differentiation. Most alterations in expression confirm or support the hypothesis of cardiomyocyte de-differentiation. Furthermore, the results suggest a role for ischemic stress in the early response of cardiomyocytes to AF, possibly via activation of hypoxia-inducible factor 1 alpha.

Original languageEnglish
Pages (from-to)427-37
Number of pages11
JournalCardiovascular Research
Volume54
Issue number2
Publication statusPublished - May 2002
Externally publishedYes

Cite this

Thijssen, V. L. J. L., van der Velden, H. M. W., van Ankeren, E. P., Ausma, J., Allessie, M. A., Borgers, M., ... Jongsma, H. J. (2002). Analysis of altered gene expression during sustained atrial fibrillation in the goat. Cardiovascular Research, 54(2), 427-37.