Research output: Contribution to journal › Article › peer-review
NOTCH1 Mutations in Aortic Stenosis : Association with Osteoprotegerin/RANK/RANKL. / Irtyuga, Olga; Malashicheva, Anna; Zhiduleva, Ekaterina; Freylikhman, Olga; Rotar, Oxana; Back, Magnus; Tarnovskaya, Svetlana; Kostareva, Anna; Moiseeva, Olga.
In: BioMed Research International, 2017.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - NOTCH1 Mutations in Aortic Stenosis
T2 - Association with Osteoprotegerin/RANK/RANKL
AU - Irtyuga, Olga
AU - Malashicheva, Anna
AU - Zhiduleva, Ekaterina
AU - Freylikhman, Olga
AU - Rotar, Oxana
AU - Back, Magnus
AU - Tarnovskaya, Svetlana
AU - Kostareva, Anna
AU - Moiseeva, Olga
PY - 2017
Y1 - 2017
N2 - Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and its ligand (RANKL) system. The purpose of the present study was to search for possible associations between NOTCH1 gene mutations and circulating levels of OPG and soluble RANKL(sRANKL) in patients with aortic stenosis (AS). Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Serum OPG and sRANKL levels were assessed. Results. In total, 6 genetic variants of the NOTCH1 gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated with NOTCH1 missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4. Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.
AB - Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and its ligand (RANKL) system. The purpose of the present study was to search for possible associations between NOTCH1 gene mutations and circulating levels of OPG and soluble RANKL(sRANKL) in patients with aortic stenosis (AS). Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Serum OPG and sRANKL levels were assessed. Results. In total, 6 genetic variants of the NOTCH1 gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated with NOTCH1 missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4. Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.
KW - VALVE INTERSTITIAL-CELLS
KW - CORONARY-ARTERY-DISEASE
KW - CALCIFICATION
KW - LIGAND
KW - ACTIVATION
KW - BIOMARKERS
KW - PATHWAY
KW - RANKL
KW - SERUM
U2 - 10.1155/2017/6917907
DO - 10.1155/2017/6917907
M3 - Article
JO - BioMed Research International
JF - BioMed Research International
SN - 2314-6133
M1 - 6917907
ER -
ID: 9457855