Novel mediators of aneurysm progression in bicuspid aortic valve disease

Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2019-07, Vol.132, p.71-83
Main Authors: Tobin, Stephanie W., Alibhai, Faisal J., Lee, Myunghyun M., Yeganeh, Azadeh, Wu, Jie, Li, Shu-Hong, Guo, Jian, Tsang, Katherine, Tumiati, Laura, Rocha, Rodolfo, Butany, Jagdish, Yau, Terrence M., Ouzounian, Maral, David, Tirone E., Weisel, Richard D., Li, Ren-Ke
Format: Article
Language:English
Subjects:
Aneurysm
Animals
Aortic Aneurysm - genetics
Aortic Aneurysm - metabolism
Aortic Aneurysm - pathology
Aortic Diseases - genetics
Aortic Diseases - metabolism
Aortic Diseases - pathology
Aortic Valve - abnormalities
Aortic Valve - physiopathology
AP-1
Bicuspid aortic valve
Bicuspid Aortic Valve Disease
Biomarkers - metabolism
Dilatation, Pathologic - genetics
Dilatation, Pathologic - metabolism
Dilatation, Pathologic - pathology
Disease Progression
Female
Gene Expression Profiling
Heart Valve Diseases - genetics
Heart Valve Diseases - metabolism
Heart Valve Diseases - pathology
Heart Valve Diseases - physiopathology
Humans
Mice
Mice, Inbred C57BL
MicroRNAs - genetics
Signal Transduction
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Summary:Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles in inflammation and endothelial cell function including cytokines and growth factors, cell surface receptors and the Activator Protein 1 (AP-1) transcription factor family (FOS, FOSB and JUN) which was chosen for further study. AP-1 was differentially expressed within paired BAV aneurysmal samples (n = 8) but not Marfan patients (n = 5). FOS protein was significantly enriched in BAV aortas compared to normal aortas but unexpectedly, ERK1/2 activity, an upstream regulator of FOS was reduced. ERK1/2 activity was restored when BAV smooth muscle cells were cultured in vitro. An mRNA-miRNA network within paired patient samples identified AP-1 as a central hub of miRNA regulation. FOS knockdown in BAV SMCs increased expression of miR-27a, a stretch responsive miRNA. AP-1 and miR-27a were also dysregulated in a mouse model of aortic constriction. In summary, this study identified a central role for AP-1 signaling in BAV aortic dilatation by using paired mRNA-miRNA patient sample. Upstream analysis of AP-1 regulation showed that the ERK1/2 signaling pathway is dysregulated and thus represents a novel chain of mediators of aortic dilatation in BAV which should be considered in future studies.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2019.04.022