ArticleThe Journal of clinical investigation2017
Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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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.
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Who cites it
28 citing papers in PubMed, 53 citations in OpenAlex.
- Uncovering Developmental Origins of Aortic Valve Disease: A Clinically Relevant Genetic Model of Aortic Stenosis.JACC. Basic to translational science · 2025Article
- Telomere Length and Clonal Hematopoiesis of Indeterminate Potential: A Loop Between Two Key Players in Aortic Valve Disease?Journal of cardiovascular development and disease · 2025Review
- The relationship between telomere length and aging-related diseases.Clinical and experimental medicine · 2025Review
- Soluble and multivalent Jag1 DNA origami nanopatterns activate Notch without pulling force.Nature communications · 2024Article
- PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves.Circulation research · 2023Article
- Congenital aortic valve stenosis: from pathophysiology to molecular genetics and the need for novel therapeutics.Frontiers in cardiovascular medicine · 2023Review
- Modeling congenital heart disease: lessons from mice, hPSC-based models, and organoids.Genes & development · 2022Review
- Article
- Causality of telomere length associated with calcific aortic valvular stenosis: A Mendelian randomization study.Frontiers in medicine · 2022Article
- Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence.International journal of molecular sciences · 2021Review
- Telomeres and Age-Related Diseases.Biomedicines · 2021Review
- Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.Stem cell reports · 2021Article
- Calcific aortic valve disease: turning therapeutic discovery up a notch.Nature reviews. Cardiology · 2021Article
- Genetic and Developmental Contributors to Aortic Stenosis.Circulation research · 2021Review
- In Vivo and In Vitro Genetic Models of Congenital Heart Disease.Cold Spring Harbor perspectives in biology · 2021Review
- Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease.Science (New York, N.Y.) · 2021Article
- Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling.Science advances · 2021Article
- NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease.Frontiers in cardiovascular medicine · 2021Review
- Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas.Frontiers in cell and developmental biology · 2021Article
- Functional genomics, genetic risk profiling and cell phenotypes in neurodegenerative disease.Neurobiology of disease · 2020Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency. Furthermore, progressive telomere shortening correlated with severity of disease, causing cardiac valve and septal disease in the neonate that was similar to the range of valve disease observed within human families. Genes that were dysregulated due to NOTCH1 haploinsufficiency in mice with shortened telomeres were concordant with proosteoblast and proinflammatory gene network alterations in human NOTCH1 heterozygous endothelial cells. These dysregulated genes were enriched for telomere-contacting promoters, suggesting a potential mechanism for telomere-dependent regulation of homeostatic gene expression. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease and provide an in vivo model in which to test therapeutic candidates targeting the progression of aortic valve disease.
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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.