Optogenetic Engineering of Atrial Cardiomyocytes

2016 ◽  
pp. 319-331 ◽  
Author(s):  
Iolanda Feola ◽  
Alexander Teplenin ◽  
Antoine A. F. de Vries ◽  
Daniël A. Pijnappels
Keyword(s):  
Atrial Cardiomyocytes

scholarly journals B-PO02-032 SUCCINATE ACCUMULATION IN ATRIAL CARDIOMYOCYTES INCREASES MITOCHONDRIAL REVERSE ELECTRON FLUX, OXIDATIVE STRESS, AND MIGHT PARTICIPATE TO AF STABILIZATION IN THE SHEEP

Heart Rhythm ◽  
2021 ◽  
Vol 18 (8) ◽  
pp. S107-S108
Author(s):  
Guido Caluori ◽  
Fanny Vaillant ◽  
Emma Abell ◽  
Farid Ichou ◽  
Virginie Loyer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Electron Flux ◽  
Atrial Cardiomyocytes

Abstract P498: Polycystin-1 Regulates Excitation-contraction Coupling In Atrial Cardiomyocytes

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Troy Hendrickson ◽  
William Perez ◽  
Vincent Provasek ◽  
Francisco J Altamirano
Keyword(s):  
Electrical Stimulation ◽  
Action Potentials ◽  
Primary Cilia ◽  
Calcium Influx ◽  
Calcium Transient ◽  
Calcium Handling ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Atrial Cardiomyocytes ◽  
Atrial Excitation

Patients with Autosomal Dominant Polycystic Kidney disease (ADPKD) have multiple cardiovascular manifestations, including increased susceptibility to arrhythmias. Mutations in polycystin-1 (PC1) encoding gene accounts for 85% cases of ADPKD, whereas mutations in polycystin-2 (PC2) only accounts for 15%. In kidney cells, PC1 interacts with PC2 to form a protein complex at the primary cilia to regulate calcium influx via PC2. However, cardiomyocytes are non-ciliated cells and the role of both PC1 and PC2 in atrial cardiomyocytes remains unknown. We have previously demonstrated that PC1 regulates action potentials and calcium handling to fine-tune ventricular cardiomyocyte contraction. Here, we hypothesize that PC1 regulates action potentials and calcium handling in atrial cardiomyocytes independent of PC2 actions. To test this hypothesis, we differentiated human induced pluripotent stem cells (iPSC) into atrial cardiomyocytes (iPSC-aCM) using previously published protocols. To determine the contribution of PC1/PC2 in atrial excitation-contraction coupling, protein expression was knocked down utilizing specific siRNA constructs, for each protein, or a universal control siRNA transfected using lipofectamine RNAiMAX. We measured action potentials using the potentiometric dye FluoVolt and intracellular calcium with Fura-2 AM or Fluo-4. Changes in fluorescence were monitored using a multiwavelength IonOptix system. iPSC-aCM were paced at 2 Hz to synchronize the beating pattern using field electrical stimulation. Our data shows that PC1 ablation significantly decreased action potential duration at 50% and 80% of repolarization, by 24% and 23%, respectively. Moreover, we observed that PC1 knockdown significantly reduced calcium transient amplitude elicited by field electrical stimulation without changes in calcium transient decay. Interestingly, PC2 knockdown did not modify calcium transients in atrial cardiomyocytes (iPSC-aCM). Our data suggest that PC1 regulates atrial excitation-contraction coupling independent of PC2 actions. This study warrants further investigation into atrial dysfunction in ADPKD patients with PC1 mutations.

A Variant Noncoding Region Regulates Prrx1 and Predisposes to Atrial Arrhythmias

2021 ◽  
Author(s):  
Fernanda M Bosada ◽  
Mathilde R Rivaud ◽  
Jae-Sun Uhm ◽  
Sander Verheule ◽  
Karel van Duijvenboden ◽  
...  
Keyword(s):  
Sodium Current ◽  
Association Studies ◽  
Noncoding Region ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Atrial Cardiomyocytes ◽  
The Impact ◽  
Lineage Specific Gene

Rationale: Atrial Fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Genome-wide association studies have identified AF-associated common variants across 100+ genomic loci, but the mechanism underlying the impact of these variant loci on AF susceptibility in vivo has remained largely undefined. One such variant region, highly associated with AF, is found at 1q24, close to PRRX1, encoding the Paired Related Homeobox 1 transcription factor. Objective: To identify the mechanistic link between the variant region at 1q24 and AF predisposition. Methods and Results: The mouse orthologue of the noncoding variant genomic region (R1A) at 1q24 was deleted using CRISPR genome editing. Among the genes sharing the topologically associated domain with the deleted R1A region (Kifap3, Prrx1, Fmo2, Prrc2c), only the broadly expressed gene Prrx1 was downregulated in mutants, and only in cardiomyocytes. Expression and epigenetic profiling revealed that a cardiomyocyte lineage-specific gene program (Mhrt, Myh6, Rbm20, Tnnt2, Ttn, Ckm) was upregulated in R1A-/- atrial cardiomyocytes, and that Mef2 binding motifs were significantly enriched at differentially accessible chromatin sites. Consistently, Prrx1 suppressed Mef2-activated enhancer activity in HL-1 cells. Mice heterozygous or homozygous for the R1A deletion were susceptible to atrial arrhythmia induction, had atrial conduction slowing and more irregular RR intervals. Isolated R1A-/- mouse left atrial cardiomyocytes showed lower action potential upstroke velocities and sodium current, as well as increased systolic and diastolic calcium concentrations compared to controls. Conclusions: The noncoding AF variant region at 1q24 modulates Prrx1 expression in cardiomyocytes. Cardiomyocyte-specific reduction of Prrx1 expression upon deletion of the noncoding region leads to a profound induction of a cardiac lineage-specific gene program and to propensity for AF. These data indicate that AF-associated variants in humans may exert AF predisposition through reduced PRRX1 expression in cardiomyocytes.

scholarly journals An elevated late INa increases the diastolic SR-Ca-leak in atrial cardiomyocytes via a CaMKII-dependent mechanism

2013 ◽  
Vol 34 (suppl 1) ◽  
pp. 5875-5875
Author(s):  
T. H. Fischer ◽  
S. Watanabe ◽  
A. F. Popov ◽  
F. Schoendube ◽  
G. Hasenfuss ◽  
...  
Keyword(s):  
Atrial Cardiomyocytes ◽  
Dependent Mechanism

Electro-Mechanical Coupling in Human Atrial Cardiomyocytes: Model Development and Analysis of Inotropic Interventions

2021 ◽  
Author(s):  
Fazeelat Mazhar ◽  
Francesco Regazzoni ◽  
Chiara Bartolucci ◽  
Cristiana Corsi ◽  
Luca Dede ◽  
...  
Keyword(s):  
Model Development ◽  
Mechanical Coupling ◽  
Atrial Cardiomyocytes

Abstract 16939: Metabolic and Electrophysiological Alterations Underlie Proarrhythmic Properties of Highly Reactive Isolevuglandins in Atrial Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tuerdi Subati ◽  
Zhenjiang Yang ◽  
Isis L Christopher ◽  
Joseph C Van Amburg ◽  
Matthew B Murphy ◽  
...  
Keyword(s):  
Membrane Potential ◽  
High Throughput Screening ◽  
Cell Metabolism ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Atp Production ◽  
Atrial Cardiomyocytes ◽  
Extracellular Flux ◽  
Mitochondrial Transition Pore

Background: Hypertension is one of the most common risk factors for atrial fibrillation (AF), although the precise cellular and molecular mechanism(s) by which hypertension leads to AF are not well understood. Isolevuglandins (IsoLGs) are highly reactive dicarbonyl products of lipid peroxidation responsible for a major component of oxidative stress-related injury. In a mouse model of hypertension, we recently demonstrated that IsoLGs are elevated in hypertensive mouse atria and that an IsoLG scavenger reduced both IsoLG burden and AF susceptibility. Hypothesis: In this study, we hypothesized that IsoLGs can promote AF by inducing proarrhythmic metabolic and electrophysiologic (EP) changes in atrial cardiomyocytes. Methods and Results: Using standard patch clamp methods, we found significant changes in action potential properties of isolated mouse atrial cardiomyocytes exposed to IsoLGs (1μM, n=15 cells), including elevation of resting membrane potential, shortening of APD and reduction of V max . Acute IsoLG treatment led to a reduction of intracellular ATP production in atrial HL-1 cardiomyocytes, as measured by using a luminescence assay. Employing TMRM and Mitotracker Green staining for confocal and high-throughput screening (HTS) live-cell imaging assays, we also found that IsoLGs decreased mitochondrial membrane potential (compared to control, TMRM fluorescence decreased by 23%, 28%, 36% and 42%, respectively, when exposed to 0.01, 0.1, 0.5 and 1μM concentrations of IsoLG) accompanied by increased apoptosis (Cell Event Caspase-3/7 Green Detection Reagent) in a concentration-dependent manner, suggesting a prolonged mitochondrial transition pore opening. Moreover, cell metabolism assays performed using Agilent’s Seahorse XF96 extracellular flux analyzer revealed that IsoLGs exert a concentration dependent decrease in basal oxygen consumption rate and ATP production in HL-1 atrial cardiomyocytes. Conclusion: Together, these findings indicate that IsoLGs promote proarrhythmic EP and mitochondrial effects in atrial cells and thus may provide a novel therapeutic target for AF.

Abstract 810: Structural and Electrophysiological Maturation of Human iPSC-Derived Atrial Cardiomyocytes to Serve as a Platform to Model Atrial Fibrillation

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Olivia T Ly ◽  
Seock Won Youn ◽  
Grace Brown ◽  
Liang Hong ◽  
Arvind Sridhar ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Atrial Cardiomyocytes ◽  
Human Ipsc

scholarly journals Empagliflozin inhibits Na + /H + exchanger activity in human atrial cardiomyocytes

2020 ◽  
Vol 7 (6) ◽  
pp. 4429-4437 ◽  
Author(s):  
Maximilian Trum ◽  
Johannes Riechel ◽  
Simon Lebek ◽  
Steffen Pabel ◽  
Samuel T. Sossalla ◽  
...  
Keyword(s):  
Atrial Cardiomyocytes
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