ArticleArteriosclerosis, thrombosis, and vascular biology2015
Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
30 citing papers in PubMed, 53 citations in OpenAlex.
- Review
- Review
- Shared Risk Factors and Molecular Mechanisms Between Aortic Stenosis and Atherosclerosis: A Rationale for Therapeutic Repositioning.International journal of molecular sciences · 2025Review
- Macrophages in Calcific Aortic Valve Disease: Paracrine and Juxtacrine Disease Drivers.Biomolecules · 2024Review
- Primary Mouse Aortic Smooth Muscle Cells Exhibit Region- and Sex-Dependent Biological Responses In Vitro.Journal of biomechanical engineering · 2024Article
- Cdh11: Roles in different diseases and potential value in disease diagnosis and treatment.Biochemistry and biophysics reports · 2023Review
- The Importance of Aortic Valve Bicuspid Phenotype in Valvular Evolution in Pediatric Patients: A Case Report and Literature Mini-Review.International journal of molecular sciences · 2023Review
- Sclerostin ablation prevents aortic valve stenosis in mice.American journal of physiology. Heart and circulatory physiology · 2022Article
- Network modeling predicts personalized gene expression and drug responses in valve myofibroblasts cultured with patient sera.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease.Frontiers in cardiovascular medicine · 2022Review
- Evaluating Medical Therapy for Calcific Aortic Stenosis: JACC State-of-the-Art Review.Journal of the American College of Cardiology · 2021Review
- Side-specific valvular endothelial-interstitial cell mechano-communication via cadherin-11.Journal of biomechanics · 2021Article
- The Complex Interplay of Inflammation, Metabolism, Epigenetics, and Sex in Calcific Disease of the Aortic Valve.Frontiers in cardiovascular medicine · 2021Review
- Notch in mechanotransduction - from molecular mechanosensitivity to tissue mechanostasis.Journal of cell science · 2020Review
- Novel loss of function mutation in NOTCH1 in a family with bicuspid aortic valve, ventricular septal defect, thoracic aortic aneurysm, and aortic valve stenosis.Molecular genetics & genomic medicine · 2020Article
- Macrophages Promote Aortic Valve Cell Calcification and Alter STAT3 Splicing.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- Notch1 suppression by microRNA-34a: a new mechanism of calcific aortic valve disease.Cardiovascular research · 2020Article
- Article
- H19 is not hypomethylated or upregulated with age or sex in the aortic valves of mice.Physiological reports · 2019Article
- Celecoxib Is Associated With Dystrophic Calcification and Aortic Valve Stenosis.JACC. Basic to translational science · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
objectiveCalcific aortic valve disease (CAVD) is a significant cardiovascular disorder, and controversy exists as to whether it is primarily a dystrophic or osteogenic process in vivo. In this study, we sought to clarify the mechanism of CAVD by assessing a genetic mutation, Notch1 heterozygosity, which leads to CAVD with 100% penetrance in humans. APPROACH AND
resultsMurine immortalized Notch1(+/-) aortic valve interstitial cells (AVICs) were isolated and expanded in vitro. Molecular signaling of wild-type and Notch1(+/-) AVICs were compared to identify changes in pathways that have been linked to CAVD-transforming growth factor-β1/bone morphogenetic protein, mitogen-activated protein kinase, and phosphoinositide 3-kinase/protein kinase B-and assessed for calcification potential. Additionally, AVIC mechanobiology was studied in a physiologically relevant, dynamic mechanical environment (10% cyclic strain) to investigate differences in responses between the cell types. We found that Notch1(+/-) AVICs resembled a myofibroblast-like phenotype expressing higher amounts of cadherin-11, a known mediator of dystrophic calcification, and decreased Runx2, a known osteogenic marker. We determined that cadherin-11 expression is regulated by Akt activity, and inhibition of Akt phosphorylation significantly reduced cadherin-11 expression. Moreover, in the presence of cyclic strain, Notch1(+/-) AVICs exhibited significantly upregulated phosphorylation of Akt at Ser473 and smooth muscle α-actin expression, indicative of a fully activated myofibroblast. Finally, these Notch1-mediated alterations led to enhanced dystrophic calcific nodule formation.
conclusionsThis study presents novel insights in our understanding of Notch1-mediated CAVD by demonstrating that the mutation leads to AVICs that are fully activated myofibroblasts, resulting in dystrophic, but not osteogenic, calcification.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.