Transthyretin amyloid fibrils alter primary fibroblast structure, function and inflammatory gene expression.

2021 ◽  
Author(s):  
Kyle T. Dittloff ◽  
Antonio Iezzi ◽  
Justin X. Zhong ◽  
Priya Mohindra ◽  
Tejal A. Desai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Structure Function ◽  
Amyloid Fibrils ◽  
Cardiac Fibroblasts ◽  
Adhesion Formation ◽  
Transthyretin Amyloidosis ◽  
Primary Fibroblast ◽  
Inflammatory Gene Expression ◽  
Age Related ◽  
Focal Adhesion Formation

Age-related wild type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. The hypothesis tested is that TTR affects cardiac fibroblasts in ways that may contribute to fibrosis. When primary cardiac fibroblasts were cultured on TTR-deposited substrates, the F-actin cytoskeleton disorganized, focal adhesion formation decreased, and nuclear shape was flattened. Fibroblasts had faster collective and single cell migration velocities on TTR-deposited substrates. Additionally, fibroblasts cultured on microposts with TTR deposition had reduced attachment and increased proliferation above untreated. Transcriptomic and proteomic analyses of fibroblasts grown on glass covered with TTR showed significant upregulation of inflammatory genes after 48 hours, indicative of progression in TTR-based diseases. Together, results suggest that TTR deposited in tissue extracellular matrix may affect both the structure, function and gene expression of cardiac fibroblasts. As therapies for wtATTR are cost-prohibitive and only slow disease progression, better understanding of cellular maladaptation may elucidate novel therapeutic targets.

scholarly journals Age-related differences in monocyte DNA methylation and immune function in healthy Kenyan adults and children

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Katherine R. Dobbs ◽  
Paula Embury ◽  
Emmily Koech ◽  
Sidney Ogolla ◽  
Stephen Munga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Young Adults ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Innate Immune ◽  
Inflammatory Gene Expression ◽  
Cpg Sites ◽  
Age Related ◽  
Adults And Children

Abstract Background Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

scholarly journals Age-related Differences in Monocyte DNA Methylation and Immune Function in Healthy Kenyan Adults and Children

2020 ◽  
Author(s):  
Katherine Rose Dobbs ◽  
Paula Embury ◽  
Emmily Koech ◽  
Sidney Ogolla ◽  
Stephen Munga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Young Adults ◽  
Innate Immune ◽  
European Ancestry ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Cpg Sites ◽  
Age Related ◽  
Adults And Children

Abstract Background: Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profi 24 les in monocytes from young adults and children from western Kenya.Results: We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles.Conclusions: These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

scholarly journals Impact of afterload and infiltration on coexisting aortic stenosis and transthyretin amyloidosis

Heart ◽  
2021 ◽  
pp. heartjnl-2021-319922 ◽  
Author(s):  
Kush P Patel ◽  
Paul Richard Scully ◽  
Christian Nitsche ◽  
Andreas A Kammerlander ◽  
George Joy ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Structure Function ◽  
Troponin T ◽  
Early Stage ◽  
Severe Aortic Stenosis ◽  
Left Ventricular ◽  
Transthyretin Amyloidosis ◽  
Age Related ◽  
Myocardial Structure ◽  
The Impact

ObjectiveThe coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype.MethodsWe compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage.ResultsCompared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) in AS-ATTR was lower than ATTR (139 (112, 167) in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179).ConclusionsThe AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial.

Molecular Mechanosensors and Focal Adhesion Mechanotransduction

2010 ◽  
Author(s):  
Mohammad R. K. Mofrad
Keyword(s):  
Gene Expression ◽  
Focal Adhesion ◽  
Cellular Response ◽  
Adhesion Formation ◽  
Structure And Function ◽  
Focal Adhesion Formation ◽  
Cytoskeletal Dynamics ◽  
Biochemical Mechanisms ◽  
And Function ◽  
Induced Changes

Cellular response to mechanical stimulation is mediated by both biochemical mechanisms via changes in gene expression and by biophysical mechanisms via mechanically induced changes in specific molecules’ structure and function. These mechanically responsive molecules can be described as the cell’s mechanosensors and can function to initiate processes such as focal adhesion formation. A series of molecular dynamics investigations explore the mechanosensor function of key molecules involved in focal adhesion formation and cytoskeletal dynamics.

Transthyretin amyloidosis and herpes zoster infection: a mimic of temporal arteritis

2021 ◽  
Vol 14 (6) ◽  
pp. e241505
Author(s):  
Mark Riley ◽  
Ammoura Ibrahim ◽  
Maria Kofman ◽  
Ruben Peredo-Wende
Keyword(s):  
Herpes Zoster ◽  
Amyloid Fibrils ◽  
Temporal Arteritis ◽  
Temporal Artery ◽  
Giant Cells ◽  
High Dose ◽  
Herpes Zoster Infection ◽  
Transthyretin Amyloidosis ◽  
Age Related ◽  
Show Evidence

We describe the case of a patient who presented with symptoms of persistent headaches, left-sided facial pain and blurry vision of the left eye. The patient had recovered from a herpes zoster infection of the V1 division of the trigeminal nerve 1 month prior. Serum inflammatory markers were elevated, raising concern for temporal arteritis. Empiric high-dose prednisone was initiated. Bilateral temporal artery biopsies were performed but did not show evidence of vasculitis or multinucleated giant cells. Instead, extracellular material deposits were present within the vessel walls. Congo red staining was diagnostic for amyloidosis. Liquid chromatography and mass spectrometry identified the amyloid fibrils to be transthyretin-type (ATTR) consistent with age-related amyloidosis. Temporal artery involvement of amyloidosis is rare but when present is most often due to light chain amyloidosis. Based on our review of the literature, only a few cases of temporal artery ATTR amyloidosis have been reported.

scholarly journals Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer

2021 ◽  
Vol 118 (35) ◽  
pp. e2025647118
Author(s):  
Kenichi Miyata ◽  
Yoshinori Imai ◽  
Satoshi Hori ◽  
Mika Nishio ◽  
Tze Mun Loo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Cellular Senescence ◽  
Noncoding Rna ◽  
Repetitive Sequences ◽  
Global Gene Expression ◽  
Chromatin Organization ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Age Related

Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non–cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

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