Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling

2019 ◽  
Author(s):  
Taku Toshima ◽  
Tetsu Watanabe ◽  
Taro Narumi ◽  
Yoichiro Otaki ◽  
Tetsuro Shishido ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Locked Nucleic Acid ◽  
Calcium Deposition ◽  
Induction Medium ◽  
Mice Model ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Related Transcription Factor ◽  
Pathway Inhibition ◽  
Human Aortic Valve

Abstract Aims Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease and is increased with elderly population. However, effective drug therapy has not been established yet. This study aimed to investigate the role of microRNAs (miRs) in the development of CAVS. Methods and results We measured the expression of 10 miRs, which were reportedly involved in calcification by using human aortic valve tissue from patients who underwent aortic valve replacement with CAVS or aortic regurgitation (AR) and porcine aortic valve interstitial cells (AVICs) after treatment with osteogenic induction medium. We investigated whether a specific miR-inhibitor can suppress aortic valve calcification in wire injury CAVS mice model. Expression of miR-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204 was decreased in valve tissues from CAVS compared with those from AR. Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine AVICs after osteogenic treatment, which was consistent with results from patients with CAVS. MiR-34a increased calcium deposition in AVICs compared with miR-control. Notch1 expression was decreased, and Runx2 expression was increased in miR-34a transfected AVICs compared with that in miR-control. Conversely, inhibition of miR-34a significantly attenuated these calcification signals in AVICs compared with miR-control. RNA pull-down assay revealed that miR-34a directly targeted Notch1 expression by binding to Notch1 mRNA 3′ untranslated region. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions. Conclusion miR-34a plays an important role in the development of CAVS via Notch1–Runx2 signalling pathway. Inhibition of miR-34a may be the therapeutic target for CAVS.

scholarly journals FP608SNF472 INHIBITS HUMAN AORTIC VALVE CALCIFICATION IN VITRO

2018 ◽  
Vol 33 (suppl_1) ◽  
pp. i247-i247
Author(s):  
Arseny Zabirnyk ◽  
Maria Bogdanova ◽  
Miguel D Ferrer ◽  
Maria Pérez ◽  
Mari-Liis Kaljusto ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

Abstract P098: Inhibitory Role of Notch1 in Calcific Aortic Valve Disease Is Mediated by Sox9

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Chetan P Hans ◽  
Asha Acharya ◽  
Sara N Koenig ◽  
Haley A Nichols ◽  
Cristi L Galindo ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Aortic Valve Disease ◽  
Notch Signaling Pathway ◽  
Valve Disease ◽  
Calcium Deposition ◽  
Aortic Valve Calcification ◽  
Calcific Aortic Valve Disease ◽  
Valve Calcification

Introduction: Aortic valve calcification is the most common form of valvular heart disease; however the mechanism(s) underlying calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. Objective: To investigate the molecular changes associated with the calcification of aortic valve that occurs with inhibition of Notch signaling. Methods and Results: The expression of Notch signaling pathway members was validated in the aortic valve cusps from adult mice, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1 signaling, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of many cartilage-specific genes that constitute the valve extracellular matrix (ECM). Analysis of these cartilage-specific genes demonstrated that several were transcriptional targets of Sox9, a master regulator of chondrogenesis, which has been previously shown to be essential for proper valve development and maintenance. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, utilizing transfection studies, addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. Conclusions: Loss of Notch signaling contributes to aortic valve calcification by a Sox9-dependent mechanism. Further elucidation of the Notch1-Sox9 molecular pathway and its role in the maintenance of the ECM will lead to an improved mechanistic understanding of aortic valve calcification and development of novel therapeutic strategies for CAVD.

scholarly journals Implication of endothelin-1 in human aortic valve calcification

2019 ◽  
Vol 11 (2) ◽  
pp. 254
Author(s):  
B. Colleville ◽  
N. Perzo ◽  
H. Eltchaninoff ◽  
V. Richard ◽  
E. Durand
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Endothelin 1 ◽  
Human Aortic Valve

Cyclophilin A inhibition as potential treatment of human aortic valve calcification

2020 ◽  
Vol 158 ◽  
pp. 104888 ◽  
Author(s):  
Gianluca L. Perrucci ◽  
Paola Songia ◽  
Donato Moschetta ◽  
Veronica A. Barbagallo ◽  
Vincenza Valerio ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Cyclophilin A ◽  
Potential Treatment ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

scholarly journals Human Aortic Valve Calcification Is Associated With an Osteoblast Phenotype

Circulation ◽  
2003 ◽  
Vol 107 (17) ◽  
pp. 2181-2184 ◽  
Author(s):  
Nalini M. Rajamannan ◽  
Malayannan Subramaniam ◽  
David Rickard ◽  
Stuart R. Stock ◽  
Janis Donovan ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

scholarly journals The inhibitory effect of Orengedokuto on human aortic valve calcification

2020 ◽  
Vol 93 (0) ◽  
pp. 2-P-211
Author(s):  
Xu Liu ◽  
Zaiqiang Yu ◽  
Wei Yang ◽  
Kazuyuki Daitoku ◽  
Shigeru Motomura ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Inhibitory Effect ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

scholarly journals Role of Noncanonical Wnt Signaling Pathway in Human Aortic Valve Calcification

2017 ◽  
Vol 37 (3) ◽  
pp. 543-552 ◽  
Author(s):  
Isabella Albanese ◽  
Bin Yu ◽  
Hamood Al-Kindi ◽  
Bianca Barratt ◽  
Leah Ott ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Aortic Valve Calcification ◽  
Valve Calcification ◽  
Human Aortic Valve

scholarly journals Comparison of Rapidly Proliferating, Multipotent Aortic Valve-Derived Stromal Cells and Valve Interstitial Cells in the Human Aortic Valve

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Yuming Huang ◽  
Kang Xu ◽  
Tingwen Zhou ◽  
Peng Zhu ◽  
Nianguo Dong ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Stromal Cells ◽  
Interstitial Cells ◽  
Culture Conditions ◽  
Stem Cell Markers ◽  
Aortic Valve Calcification ◽  
Ki 67 ◽  
Valve Calcification ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve

Aortic valve calcification is a common clinical disease, caused by valve interstitial cells (VICs), which initiate the thickening and then calcification of valve leaflets. Classical valve-derived cells can be seen in different cell populations according to their different morphologies, but it is not clear whether different types of mesenchymal cells exist. In this study, culture conditions for mesenchymal stromal cells were used to selectively isolate valve-derived stromal cells (VDSCs). After subculturing, the morphology, proliferation, multidifferentiation, immunophenotype, and gene expression profiling in isolated VDSCs were compared with those in conventional cultured VICs. VDSCs isolated from human aortic valves were uniform spindle-shaped fibroblasts, had mutilineage differentiation abilities, and proliferated faster than VICs. Classic mesenchymal markers including cluster of differentiation 90 (CD90), CD44, and CD29 were positively expressed. In addition, the stem cell markers CD163, CD133, and CD106 were all expressed in VDSCs. RNA-sequencing identified 1595 differentially expressed genes between VDSCs and VICs of which 301 were upregulated and 1294 were downregulated. Valvular extracellular matrix genes of VDSCs such as collagen type 1, alpha 1 (COL1A1), COL1A2, and fibronectin 1 were abundantly expressed. In addition, runt-related transcription factor 2 and Ki-67 proteins were also markedly upregulated in VDSCs, whereas there was less expression of the focal adhesion genes integrin alpha and laminin alpha in VDSCs compared to VICs. In conclusion, novel rapidly proliferating VDSCs with fibroblast morphology, which were found to express mesenchymal and osteogenic markers, may contribute to aortic valve calcification.

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