scholarly journals Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?

2019 ◽  
Vol 20 (16) ◽  
pp. 3986 ◽  
Author(s):  
Francesco Moccia ◽  
Francesco Lodola ◽  
Ilaria Stadiotti ◽  
Chiara Assunta Pilato ◽  
Milena Bellin ◽  
...  
Keyword(s):  
Cardiac Contractility ◽  
Induced Pluripotent Stem Cell ◽  
Arrhythmogenic Cardiomyopathy ◽  
Mechanical Coupling ◽  
Plakophilin 2 ◽  
Genes Encoding ◽  
Life Threatening ◽  
Delayed Afterdepolarizations ◽  
Induced Pluripotent

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+ handling machinery, focusing on the available data supporting this hypothesis. The Ca2+ toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation‒contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+ signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease.

scholarly journals Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Saara Marttila ◽  
Leena E. Viiri ◽  
Pashupati P. Mishra ◽  
Brigitte Kühnel ◽  
Pamela R. Matias-Garcia ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Methylation Status ◽  
Induced Pluripotent Stem Cell ◽  
Methylation Pattern ◽  
Rna Expression ◽  
Non Coding Rna ◽  
Mother’S Age ◽  
Induced Pluripotent ◽  
Metastable Epiallele

Abstract Background Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines. Results We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual’s methylation status is associated with the mother’s age and socioeconomic status, but not with the individual’s own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood. Conclusions These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.

scholarly journals Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients

2019 ◽  
Vol 20 (15) ◽  
pp. 3773 ◽  
Author(s):  
Mostafa Kiamehr ◽  
Alexa Klettner ◽  
Elisabeth Richert ◽  
Ali Koskela ◽  
Arto Koistinen ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Diabetic Patients ◽  
Rpe Cells ◽  
Normal Glucose ◽  
Healthy Control ◽  
Induced Pluripotent ◽  
Type 2 Diabetic

In diabetic patients, high blood glucose induces alterations in retinal function and can lead to visual impairment due to diabetic retinopathy. In immortalized retinal pigment epithelial (RPE) cultures, high glucose concentrations are shown to lead to impairment in epithelial barrier properties. For the first time, the induced pluripotent stem-cell-derived retinal pigment epithelium (hiPSC-RPE) cell lines derived from type 2 diabetics and healthy control patients were utilized to assess the effects of glucose concentration on the cellular functionality. We show that both type 2 diabetic and healthy control hiPSC-RPE lines differentiate and mature well, both in high and normal glucose concentrations, express RPE specific genes, secrete pigment epithelium derived factor, and form a polarized cell layer. Here, type 2 diabetic hiPSC-RPE cells had a decreased barrier function compared to controls. Added insulin increased the epithelial cell layer tightness in normal glucose concentrations, and the effect was more evident in type 2 diabetics than in healthy control hiPSC-RPE cells. In addition, the preliminary functionality assessments showed that type 2 diabetic hiPSC-RPE cells had attenuated autophagy detected via ubiquitin-binding protein p62/Sequestosome-1 (p62/SQSTM1) accumulation, and lowered pro- matrix metalloproteinase 2 (proMMP2) as well as increased pro-MMP9 secretion. These results suggest that the cellular ability to tolerate stress is possibly decreased in type 2 diabetic RPE cells.

scholarly journals Generation of human induced pluripotent stem cell line from a patient with a long QT syndrome type 2

2016 ◽  
Vol 16 (2) ◽  
pp. 304-307 ◽  
Author(s):  
Azra Fatima ◽  
Dina Ivanyuk ◽  
Stefan Herms ◽  
Stefanie Heilmann-Heimbach ◽  
Orla O'Shea ◽  
...  
Keyword(s):  
Stem Cell ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Syndrome Type ◽  
Stem Cell Line ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent
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