A Kostina1, A Shishkova2, E Ignatieva2, O Irtyuga2, M Bogdanova3, K Levchuk2, A Golovkin2, E Zhiduleva2, V Uspenskiy2, O Moiseeva2, G Faggian4, J Vaage5, A Kostareva6, A Rutkovskiy7, A Malashicheva8. 1. National Almazov Medical Research Centre, Saint-Petersburg, Russia; University of Verona, Verona, Italy; ITMO University, Institute of translational Medicine, St. Petersburg, Russia. 2. National Almazov Medical Research Centre, Saint-Petersburg, Russia. 3. National Almazov Medical Research Centre, Saint-Petersburg, Russia; Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway. 4. University of Verona, Verona, Italy. 5. ITMO University, Institute of translational Medicine, St. Petersburg, Russia; Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway. 6. National Almazov Medical Research Centre, Saint-Petersburg, Russia; ITMO University, Institute of translational Medicine, St. Petersburg, Russia. 7. Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway; Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway. 8. National Almazov Medical Research Centre, Saint-Petersburg, Russia; ITMO University, Institute of translational Medicine, St. Petersburg, Russia; Saint Petersburg State University, Saint-Petersburg, Russia. Electronic address: malashicheva_ab@almazovcentre.ru.
Abstract
AIMS: Calcific aortic valve disease is the most common heart valve disease in the Western world. Bicuspid and tricuspid aortic valve calcifications are traditionally considered together although the dynamics of the disease progression is different between the two groups of patients. Notch signaling is critical for bicuspid valve development and NOTCH1 mutations are associated with bicuspid valve and calcification. We hypothesized that Notch-dependent mechanisms of valve mineralization might be different in the two groups. METHODS AND RESULTS: We used aortic valve interstitial cells and valve endothelial cells from patients with calcific aortic stenosis with bicuspid or tricuspid aortic valve. Expression of Notch-related genes in valve interstitial cells by qPCR was different between bicuspid and tricuspid groups. Discriminant analysis of gene expression pattern in the interstitial cells revealed that the cells from calcified bicuspid valves formed a separate group from calcified tricuspid and control cells. Interstitial cells from bicuspid calcified valves demonstrated significantly higher sensitivity to stimuli at early stages of induced proosteogenic differentiation and were significantly more sensitive to the activation of proosteogenic OPN, ALP and POSTIN expression by Notch activation. Notch-activated endothelial-to-mesenchymal transition and the corresponding expression of HEY1 and SLUG were also more prominent in bicuspid valve derived endothelial cells compared to the cells from calcified tricuspid and healthy valves. CONCLUSION: Early signaling events including Notch-dependent mechanisms that are responsible for the initiation of aortic valve calcification are different between the patients with bicuspid and tricuspid aortic valves.
AIMS: Calcific aortic valve disease is the most common heart valve disease in the Western world. Bicuspid and tricuspid aortic valve calcifications are traditionally considered together although the dynamics of the disease progression is different between the two groups of patients. Notch signaling is critical for bicuspid valve development and NOTCH1 mutations are associated with bicuspid valve and calcification. We hypothesized that Notch-dependent mechanisms of valve mineralization might be different in the two groups. METHODS AND RESULTS: We used aortic valve interstitial cells and valve endothelial cells from patients with calcific aortic stenosis with bicuspid or tricuspid aortic valve. Expression of Notch-related genes in valve interstitial cells by qPCR was different between bicuspid and tricuspid groups. Discriminant analysis of gene expression pattern in the interstitial cells revealed that the cells from calcified bicuspid valves formed a separate group from calcified tricuspid and control cells. Interstitial cells from bicuspid calcified valves demonstrated significantly higher sensitivity to stimuli at early stages of induced proosteogenic differentiation and were significantly more sensitive to the activation of proosteogenic OPN, ALP and POSTIN expression by Notch activation. Notch-activated endothelial-to-mesenchymal transition and the corresponding expression of HEY1 and SLUG were also more prominent in bicuspid valve derived endothelial cells compared to the cells from calcified tricuspid and healthy valves. CONCLUSION: Early signaling events including Notch-dependent mechanisms that are responsible for the initiation of aortic valve calcification are different between the patients with bicuspid and tricuspid aortic valves.
Authors: Martha E Floy; Sophie E Givens; Oriane B Matthys; Taylor D Mateyka; Charles M Kerr; Alexandra B Steinberg; Ana C Silva; Jianhua Zhang; Ying Mei; Brenda M Ogle; Todd C McDevitt; Timothy J Kamp; Sean P Palecek Journal: FASEB J Date: 2021-09 Impact factor: 5.834
Authors: Francesco Vieceli Dalla Sega; Francesca Fortini; Paolo Cimaglia; Luisa Marracino; Elisabetta Tonet; Antonio Antonucci; Marco Moscarelli; Gianluca Campo; Paola Rizzo; Roberto Ferrari Journal: Int J Mol Sci Date: 2020-11-24 Impact factor: 5.923
Authors: Francesco Vieceli Dalla Sega; Francesca Fortini; Paolo Severi; Paola Rizzo; Iija Gardi; Paolo Cimaglia; Claudio Rapezzi; Luigi Tavazzi; Roberto Ferrari Journal: Biology (Basel) Date: 2022-03-09