Premium
The mir‐200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves
Author(s) -
Maleki S.,
Cottrill K. A.,
Poujade F.A.,
Bhattachariya A.,
Bergman O.,
Gådin J. R.,
Simon N.,
Lundströmer K.,
FrancoCereceda A.,
Björck H. M.,
Chan S. Y.,
Eriksson P.
Publication year - 2019
Publication title -
journal of internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.625
H-Index - 160
eISSN - 1365-2796
pISSN - 0954-6820
DOI - 10.1111/joim.12833
Subject(s) - bicuspid aortic valve , ascending aorta , aortic valve , aortic aneurysm , aneurysm , population , gene expression , medicine , aorta , gene , cardiology , biology , microbiology and biotechnology , genetics , surgery , environmental health
Background An individual with a bicuspid aortic valve ( BAV ) runs a substantially higher risk of developing aneurysm in the ascending aorta compared to the normal population with tricuspid aortic valves ( TAV ). Aneurysm formation in patients with BAV and TAV is known to be distinct at the molecular level but the underlying mechanisms are undefined. Here, we investigated the still incompletely described role of micro RNA s (mi RNA s), important post‐transcriptional regulators of gene expression, in such aortic disease of patients with BAV as compared with TAV . Methods and Results Using a system biology approach, based on data obtained from proteomic analysis of non‐dilated aortas from BAV and TAV patients, we constructed a gene‐interaction network of regulatory micro RNA s associated with the observed differential protein signature. The miR‐200 family was the highest ranked mi RNA , hence potentially having the strongest effect on the signalling network associated with BAV . Further, qRT ‐ PCR and Ch IP analyses showed lower expression of miR‐200c, higher expression of miR‐200 target genes, ZEB 1/ ZEB 2 transcription factors, and higher chromatin occupancy of the miR‐200c promoter by ZEB 1/ ZEB 2 in BAV patients, indicating a miR‐200c/ ZEB s negative feedback loop and induction of endothelial/epithelial mesenchymal transition (End MT / EMT ). Conclusion We propose that a miR‐200‐dependent process of End MT / EMT is a plausible biological mechanism rendering the BAV ascending aorta more prone to aneurysm development. Although initially supported by a miR‐200c/ ZEB feedback loop, this process is most probably advanced by cooperation of other mi RNA s.