HSPB1, HSPB6, HSPB7 and HSPB8 Protect against RhoA GTPase-Induced Remodeling in Tachypaced Atrial Myocytes

BACKGROUND: We previously demonstrated the small heat shock protein, HSPB1, to prevent tachycardia remodeling in in vitro and in vivo models for Atrial Fibrillation (AF). To gain insight into its mechanism of action, we examined the protective effect of all 10 members of the HSPB family on tachycardia remodeling. Furthermore, modulating effects of HSPB on RhoA GTPase activity and F-actin stress fiber formation were examined, as this pathway was found of prime importance in tachycardia remodeling events and the initiation of AF. METHODS AND RESULTS: Tachypacing (4 Hz) of HL-1 atrial myocytes significantly and progressively reduced the amplitude of Ca²⁺ transients (CaT). In addition to HSPB1, also overexpression of HSPB6, HSPB7 and HSPB8 protected against tachypacing-induced CaT reduction. The protective effect was independent of HSPB1. Moreover, tachypacing induced RhoA GTPase activity and caused F-actin stress fiber formation. The ROCK inhibitor Y27632 significantly prevented tachypacing-induced F-actin formation and CaT reductions, showing that RhoA activation is required for remodeling. Although all protective HSPB members prevented the formation of F-actin stress fibers, their mode of action differs. Whilst HSPB1, HSPB6 and HSPB7 acted via direct prevention of F-actin formation, HSPB8-protection was mediated via inhibition of RhoA GTPase activity. CONCLUSION: Overexpression of HSPB1, as well as HSPB6, HSPB7 and HSPB8 independently protect against tachycardia remodeling by attenuation of the RhoA GTPase pathway at different levels. The cardioprotective role for multiple HSPB members indicate a possible therapeutic benefit of compounds able to boost the expression of single or multiple members of the HSPB family

Atrial arrhythmogenicity in aged Scn5a+/∆KPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction

Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/∆KPQ mice modeling long QT3 syndrome in relationship to cardiac Na+ channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/∆KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/ΔKPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/ΔKPQ than young WT. These levels increased with age in WT but not Scn5a+/ΔKPQ. Both young and aged Scn5a+/ΔKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/ΔKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/ΔKPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/ΔKPQ. Aged murine Scn5a+/ΔKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/ΔKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/ΔKPQ hearts

Оценка качества образования на основе компетентностного подхода

В работе представлен практический опыт оценки качества образования в новом формате компетентностного подход

Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization

Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Correction to article number 15805 published in June 2017 in Nature Communications, vol 8

Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Correction to article number 15805 published in June 2017 in Nature Communications, vol 8

Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation

Objective: Atrial fibrillation (AF) is a progressive disease. Previously, clinical and animal experimental studies in AF revealed a variety of myocyte remodeling processes including L-type Ca(2+) channel reduction and structural changes, which finally result in electrical remodeling and contractile dysfunction. There are indications that myocyte remodeling is mediated by Ca(2+) overload induced calpain activation. To study in more detail the mechanisms underlying myocyte remodeling and to develop strategies for drug-interference, we utilised a paced cell model for AF. Methods and results: HL-1 atrial myocytes were subjected to a 10 times increase in rate over basal values by electrical field stimulation at 5 Hz. It was found that 24-h pacing reduced plasmalemmal levels of L-type Ca(2+) channel alpha1C subunit by - 72% compared to controls. No changes in amount of the potassium channel Subunits Kv4.3 and Kv1.5 were found. Pacing also induced marked structural changes; myolysis and nuclear condensation, paralleled by a 14-fold increase in calpain activity. The pacing-induced reduction of L-type Ca(2+) channel protein was fully prevented by treatment with verapamil, the active stereoisomer of methoxyverapamil D600, the calpain inhibitors PD150606 and E64d, and LaCl(3). Interestingly, PD150606, E64d and LaCl(3), but not (methoxy)verapamil, prevented structural changes. Conclusions: Paced HL-1 atrial myocytes undergo myocyte remodeling similar to that found in myocytes from patients with AF Calcium influx independent of the L-type Ca(2+) channel and subsequent activation of calpain represent key features in the progression towards overt structural changes. Calpain inhibition may therefore represent a useful lead for therapeutic intervention in AF. (C) 2004 European Society of Cardiology. published by Elsevier B.V. All rights reserved

Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs

Background: There is evidence suggesting involvement of oxidative stress, inflammation, and calcineurin/nuclear factor of activated T cell pathways in atrial fibrillation. This study evaluated the efficacy of anti-inflammatory and calcineurin-inhibitory drugs on promotion of atrial fibrillation by atrial tachycardia-induced remodeling in dogs. Methods and results: Dogs were subjected to atrial tachypacing at 400 bpm in the absence and presence of treatment with prednisone (15 or 50 mg/day) or ibuprofen (anti-inflammatory) or cyclosporine-A (calcineurin inhibitor). Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. A final open-chest study was performed on day 8. Serum G reactive protein was measured by ELISA and nitric oxide synthase by Western blotting. The mean duration of induced atrial fibrillation was markedly increased by tachypacing alone, from 26 +/- 8 to 962 +/- 317 s (p <0.0 1), and the atrial effective refractory period was decreased from 117 +/- 4 to 73 +/- 7 ms (p <0.001; cycle-length 300 ms). Tachypacing-induced effective refractory period shortening and atrial fibrillation promotion were unaffected by ibuprofen or cyclosporine-A; however, both doses of prednisone suppressed tachypacing-remodeling effects (atrial fibrillation duration to 96 60 s and 28 +/- 11 s at higher and lower doses, respectively; effective refractory period to 101 +/- 6 ms for higher-dose and 105 +/- 3 ms for lower-dose group). In addition, prednisone (but not ibuprofen or cyclosporine) significantly decreased C-reactive protein concentrations and attenuated the increase in endothelial nitric oxide synthase expression caused by atrial tachypacing. Conclusions: Prednisone prevents the electrophysiological and atrial fibrillation-promoting effects of atrial tachycardia-remodeling, possibly by an anti-inflammatory action, whereas the less potent anti-inflammatory ibuprofen and the calcineurin inhibitor cyclosporine-A are without effect. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved