Atrial Fibrillation Complicated by Heart Failure Induces Distinct Remodeling of Calcium Cycling Proteins

Lugenbiel, Patrick; Wenz, Fabian; Govorov, Katharina; Schweizer, Patrick; Katus, Hugo A.; Thomas, Dierk

doi:10.1371/journal.pone.0116395

Cited by 38 publications

(37 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following the development of cardiac or vascular pathology the contractile requirements of the heart are severely increased in order to adequately compensate for the diseased tissue. The abundance of LTCC is reduced and the channel becomes hyperphosphorylated (Chen, 2002 ; Lugenbiel et al, 2015 ), RyR2 are similarly hyperphosphorylated (Ai et al, 2005 ; Shan et al, 2010a ), SERCA expression is reduced (Hasenfuss et al, 1994 ) as is its activity by hypo-phosphorylation of phospholamban (PLB) (Reiken et al, 2003 ) while NCX extrusion of Ca 2+ is increased (Lugenbiel et al, 2015 ). The net impact of this, as seen in myocytes from failing hearts, is a reduced ability to drive Ca 2+ into the cytoplasm and SR, therefore limiting Ca 2+ release during systole and increasing its accumulation during diastole.…”

Section: Excitation Contraction Couplingmentioning

confidence: 99%

Ca2+ signaling in the myocardium by (redox) regulation of PKA/CaMKII

Johnston¹,

Lehnart²,

Burgoyne

2015

Front. Pharmacol.

View full text Add to dashboard Cite

Homeostatic cardiac function is maintained by a complex network of interdependent signaling pathways which become compromised during disease progression. Excitation-contraction-coupling, the translation of an electrical signal to a contractile response is critically dependent on a tightly controlled sequence of events culminating in a rise in intracellular Ca2+ and subsequent contraction of the myocardium. Dysregulation of this Ca2+ handling system as well as increases in the production of reactive oxygen species (ROS) are two major contributing factors to myocardial disease progression. ROS, generated by cellular oxidases and by-products of cellular metabolism, are highly reactive oxygen derivatives that function as key secondary messengers within the heart and contribute to normal homeostatic function. However, excessive production of ROS, as in disease, can directly interact with kinases critical for Ca2+ regulation. This post-translational oxidative modification therefore links changes in the redox status of the myocardium to phospho-regulated pathways essential for its function. This review aims to describe the oxidative regulation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and cAMP-dependent protein kinase A (PKA), and the subsequent impact this has on Ca2+ handling within the myocardium. Elucidating the impact of alterations in intracellular ROS production on Ca2+ dynamics through oxidative modification of key ROS sensing kinases, may provide novel therapeutic targets for preventing myocardial disease progression.

show abstract

Section: Excitation Contraction Couplingmentioning

confidence: 99%

Ca2+ signaling in the myocardium by (redox) regulation of PKA/CaMKII

Johnston¹,

Lehnart²,

Burgoyne

2015

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…In conclusion, dyssynchrony of Ca release (19) and Ca removal (17,20) has emerged as an important feature of heart failure pathophysiology, in both ventricular and atrial tissue. Remodeling of NCX plays a central role in this process (16,29) and is equally important as cause of the dyssynchrony and the (related) enhanced propensity of arrhythmias in HF. Thus, because of its central role, NCX inhibition might be a valid approach to mitigate enhanced arrhythmia susceptibility in HF.…”

Section: Discussionmentioning

confidence: 99%

Dyssynchronous calcium removal in heart failure-induced atrial remodeling

Hohendanner

DeSantiago

Heinzel

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

We tested the hypothesis that in atrial myocytes from a rabbit left ventricular heart failure (HF) model, spatial inhomogeneity and temporal dyssynchrony of Ca removal during excitation-contraction coupling together with increased Na/Ca exchange (NCX) activity generate a substrate for proarrhythmic Ca release. Ca removal occurs via Ca reuptake into the sarcoplasmic reticulum and extrusion via NCX exclusively in the cell periphery since rabbit atrial myocytes lack transverse tubules. Ca removal kinetics were assessed by the time constant τ of decay of local peripheral subsarcolemmal (SS) and central (CT) action potential (AP)-induced Ca transients (CaTs) recorded in confocal line scan mode (using Fluo-4). Spatial and temporal dyssynchrony of Ca removal was quantified by CV TAU, defined as the standard deviation of local τ along the transverse cell axis divided by mean τ. In normal cells CT CaT decline was slower compared with the SS domain, while in HF cells decline was accelerated, became equal in SS and CT regions, and a significant increase of CV TAU indicated an increased Ca removal dyssynchrony. In HF atrial cells NCX upregulation was accompanied by an overall higher incidence of spontaneous Ca waves and a higher propensity of arrhythmogenic Ca waves, defined as waves that triggered APs due to NCX-mediated membrane depolarization. NCX inhibition normalized CV TAU in HF atrial cells and decreased the propensity of Ca waves. In summary, HF atrial myocytes show accelerated but dyssynchronous diastolic Ca removal and altered sarcoplasmic reticulum Ca-ATPase (SERCA) and NCX activity that result in increased susceptibility to arrhythmia.

show abstract

“…Protein immunodetection was performed by sodium dodecyl sulfate (SDS) gel electrophoresis and Western blotting [38,39]. HL-1 cells were lysed in radioimmunoprecipitation (RIPA) buffer containing 20 mM Tris-HCl, 0.5% NP-40, 0.5% sodium-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM Na 3 VO 4 , 1 mM NaF, and inhibitors of proteases (Complete) and phosphatases (PhosStop) (Roche Applied Science, Indianapolis, IN, USA).…”

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Lugenbiel

Govorov

Rahm

et al. 2018

Cell Physiol Biochem

Self Cite

View full text Add to dashboard Cite

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K⁺ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD₉₀ in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K⁺ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K⁺ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

show abstract

Atrial Fibrillation Complicated by Heart Failure Induces Distinct Remodeling of Calcium Cycling Proteins

Cited by 38 publications

References 35 publications

Ca2+ signaling in the myocardium by (redox) regulation of PKA/CaMKII

Ca2+ signaling in the myocardium by (redox) regulation of PKA/CaMKII

Dyssynchronous calcium removal in heart failure-induced atrial remodeling

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Contact Info

Product

Resources

About