ArticleBioscience reports2015
Amyloidogenic and non-amyloidogenic transthyretin variants interact differently with human cardiomyocytes: insights into early events of non-fibrillar tissue damage.
Article in Bioscience reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 35 citations in OpenAlex.
- Clinical Factors Related to Cardiac Conduction Disturbance in Patients With Wild-Type Transthyretin Amyloid Cardiomyopathy Undergoing Tafamidis Treatment.Circulation reports · 2026Article
- Development of Human iPSC-based Microphysiogical Models of Transthyretin Amyloid Cardiomyopathy.Research square · 2026Article
- Mechanisms of damage and therapies for cardiac amyloidosis: a role for inflammation?Clinical research in cardiology : official journal of the German Cardiac Society · 2026Review
- Disease Prognosis and Progression in Transthyretin Amyloidosis: JACC: CardioOncology State-of-the-Art Review.JACC. CardioOncology · 2026Review
- Human-Induced Pluripotent Stem Cell Models for Amyloid Cardiomyopathy: From Mechanistic Insights to Therapeutic Discovery.Journal of cardiovascular development and disease · 2025Review
- In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls, and potential.Cardiovascular research · 2025Review
- Uncovering cell type-specific phenotypes using a novel human in vitro model of transthyretin amyloid cardiomyopathy.Stem cell research & therapy · 2025Article
- Echocardiographic risk stratification in light chain and transthyretin amyloidosis: a meta-analysis.European heart journal open · 2025Article
- Associations between pathophysiological traits and symptom development in retrospective analysis of V30M and V122I transthyretin amyloidosis.International journal of cardiology. Heart & vasculature · 2025Article
- Article
- Cardiac Amyloidosis: State-of-the-Art Review in Molecular Pathology.Current issues in molecular biology · 2024Review
- Sex Differences in Transthyretin Cardiac Amyloidosis: Unraveling the Complexities in Epidemiology, Pathophysiology, Diagnosis, and Treatment.Current heart failure reports · 2024Review
- Cardiac Troponin in Patients With Light Chain and Transthyretin Cardiac Amyloidosis:JACC. CardioOncology · 2024Review
- Targeted treatments of AL and ATTR amyloidosis.Heart failure reviews · 2022Review
- Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function.Journal of personalized medicine · 2022Article
- Atrial function and geometry differences in transthyretin versus immunoglobulin light chain amyloidosis: a cardiac magnetic resonance study.Scientific reports · 2022Article
- Molecular Mechanisms of Cardiac Amyloidosis.International journal of molecular sciences · 2021Review
- Transthyretin amyloid fibrils alter primary fibroblast structure, function, and inflammatory gene expression.American journal of physiology. Heart and circulatory physiology · 2021Article
- Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis.Circulation research · 2021Review
- Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity.Molecules (Basel, Switzerland) · 2020Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
TTR (transthyretin) amyloidoses are diseases characterized by the aggregation and extracellular deposition of the normally soluble plasma protein TTR. Ex vivo and tissue culture studies suggest that tissue damage precedes TTR fibril deposition, indicating that early events in the amyloidogenic cascade have an impact on disease development. We used a human cardiomyocyte tissue culture model system to define these events. We previously described that the amyloidogenic V122I TTR variant is cytotoxic to human cardiac cells, whereas the naturally occurring, stable and non-amyloidogenic T119M TTR variant is not. We show that most of the V122I TTR interacting with the cells is extracellular and this interaction is mediated by a membrane protein(s). In contrast, most of the non-amyloidogenic T119M TTR associated with the cells is intracellular where it undergoes lysosomal degradation. The TTR internalization process is highly dependent on membrane cholesterol content. Using a fluorescent labelled V122I TTR variant that has the same aggregation and cytotoxic potential as the native V122I TTR, we determined that its association with human cardiomyocytes is saturable with a KD near 650 nM. Only amyloidogenic V122I TTR compete with fluorescent V122I for cell-binding sites. Finally, incubation of the human cardiomyocytes with V122I TTR but not with T119M TTR, generates superoxide species and activates caspase 3/7. In summary, our results show that the interaction of the amyloidogenic V122I TTR is distinct from that of a non-amyloidogenic TTR variant and is characterized by its retention at the cell membrane, where it initiates the cytotoxic cascade.
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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.