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Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve
Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden.
Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Sweden.
Computational Medicine, Karolinska Institutet, Stockholm.
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2013 (English)In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 91, no 1, 129-139 p.Article in journal (Refereed) Published
Abstract [en]

Rationale: Individuals with bicuspid aortic valve (BAV) are at significantly higher risk of developing serious aortic complications including aortic aneurysm and dissection than individuals with a tricuspid aortic valve (TAV). Studies have indicated an altered aortic blood flow in patients with BAV, however the extent to which altered flow may influence the pathological state of BAV aorta is still unclear.

Objective: To dissect flow-mediated gene expression potentially leading to increased aneurysm susceptibility in patients with BAV.

Methods and Results: A large collection of publically available microarray data sets were screened for consistent co-expression with KLF2, KLF4, TIE1, THBD, and PKD2, five previously well-characterized flow-regulated genes. This identified 122 genes with coexpression probability of >0.5. Of these, 44 genes satisfied two additional filtering criteria in ascending aorta (127 arrays). The criteria were significant correlation with one or more of the 5 query genes (R>0.40) and differential expression between patients with BAV and TAV. No gene fulfilled the criteria in mammary artery (88 arrays). A large proportion of the identified genes were angiogenesis related genes. Further, 55% of the genes differentially expressed between BAV and TAV showed differential expression in disturbed vs. uniform flow pattern regions in rat aorta. Protein expression of ZFP36, PKD2 and GPR116 were analyzed by immunohistochemistry and their association with BAV were further discussed.

Conclusions: With a new strategy to dissect flow-mediated gene expression, we identified novel genes associated with valve morphology. The complex pattern of blood flow, as a consequence of BAV

Place, publisher, year, edition, pages
Springer-Verlag New York, 2013. Vol. 91, no 1, 129-139 p.
Keyword [en]
Aneurysm, gene expression, aorta, impaired flow, angiogenesis
National Category
URN: urn:nbn:se:liu:diva-73956DOI: 10.1007/s00109-012-0942-8ISI: 000313077000013OAI: diva2:479274
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2014-01-17
In thesis
1. Vessel wall integrity: influence of genetics and flow
Open this publication in new window or tab >>Vessel wall integrity: influence of genetics and flow
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow.

The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease.

Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women.

Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca2+ signalling were among the most highly differentially expressed. Up-regulation of Ca2+-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall.

Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 84 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1270
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-73958 (URN)978‐91‐7393‐033‐8 (ISBN)
Public defence
2012-01-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:15 (Swedish)
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2013-10-25Bibliographically approved

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Björck, Hanna M.Renner, JohanLänne, Toste
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Center for Medical Image Science and Visualization (CMIV)PhysiologyFaculty of Health SciencesApplied Thermodynamics and Fluid MechanicsThe Institute of TechnologyDepartment of Thoracic and Vascular Surgery
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