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Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel.

ABSTRACT: Autophagy, a bidirectional degradative process extensively occurring in eukaryotes, has been revealed as a potential therapeutic target for several cardiovascular diseases. However, its role in atrial fibrillation (AF) remains largely unknown. This study aimed to determine the role of autophagy in atrial electrical remodeling under AF condition. Here, we reported that autophagic flux was markedly activated in atria of persistent AF patients and rabbit model of atrial rapid pacing (RAP). We also observed that the key autophagy-related gene7 (ATG7) significantly upregulated in AF patients as well as tachypacing rabbits. Moreover, lentivirus-mediated ATG7 knockdown and overexpression in rabbits were employed to clarify the effects of autophagy on atrial electrophysiology via intracardiac operation and patch-clamp experiments. Lentivirus-mediated ATG7 knockdown or autophagy inhibitor chloroquine (CQ) restored the shortened atrial effective refractory period (AERP) and alleviated the AF vulnerability caused by tachypacing in rabbits. Conversely, ATG7 overexpression significantly promoted the incidence and persistence of AF and decreased L-type calcium channel (Cav1.2 ?-subunits), along with abbreviated action potential duration (APD) and diminished L-type calcium current (I_Ca,L). Furthermore, the co-localization and interaction of Cav1.2 with LC3B-positive autophagosomes enhanced when autophagy was activated in atrial myocytes. Tachypacing-induced autophagic degradation of Cav1.2 required ubiquitin signal through the recruitment of ubiquitin-binding proteins RFP2 and p62, which guided Cav1.2 to autophagosomes. These findings suggest that autophagy induces atrial electrical remodeling via ubiquitin-dependent selective degradation of Cav1.2 and provide a novel and promising strategy for preventing AF development.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC6115437 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel.

Yuan Yue Y Zhao Jing J Gong Yongtai Y Wang Dingyu D Wang Xiaoyu X Yun Fengxiang F Liu Zhaorui Z Zhang Song S Li Wenpeng W Zhao Xinbo X Sun Li L Sheng Li L Pan Zhenwei Z Li Yue Y

Cell death & disease 20180829 9

Autophagy, a bidirectional degradative process extensively occurring in eukaryotes, has been revealed as a potential therapeutic target for several cardiovascular diseases. However, its role in atrial fibrillation (AF) remains largely unknown. This study aimed to determine the role of autophagy in atrial electrical remodeling under AF condition. Here, we reported that autophagic flux was markedly activated in atria of persistent AF patients and rabbit model of atrial rapid pacing (RAP). We also ...[more]

PMID: 30158642

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Project description:AIMS:Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC inhibition on such remodelling is unknown. Here, we investigated the ability of a clinically available Ca2+-channel blocker (CCB) with NTCC-blocking activity to suppress the arrhythmogenic effects of AF-promoting remodelling in dogs. METHODS AND RESULTS:Mongrel dogs were kept in AF by right atrial tachypacing at 600 bpm. Four groups were studied under short-term AF (7 days): (i) Shams, instrumented but without tachypacing (n = 5); (ii) a placebo group, tachypaced while receiving placebo (n = 6); (iii) a control tachypacing group receiving nifedipine (10 mg orally twice-daily; n = 5), an L-type CCB; and (iv) a cilnidipine group, subjected to tachypacing and treatment with cilnidipine (10 mg orally twice-daily; n = 7), an N-/L-type CCB. With cilnidipine therapy, dogs with 1-week AF showed significantly reduced autonomic changes reflected by heart rate variability (decreases in RMSSD and pNN50) and plasma norepinephrine concentrations. In addition, cilnidipine-treated dogs had decreased extracellular matrix gene expression vs. nifedipine-dogs. As in previous work, atrial fibrosis had not yet developed after 1-week AF, so three additional groups were studied under longer-term AF (21 days): (i) Shams, instrumented without tachypacing or drug therapy (n = 8); (ii) a placebo group, tachypaced while receiving placebo (n = 8); (iii) a cilnidipine group, subjected to tachypacing during treatment with cilnidipine (10 mg twice-daily; n = 8). Cilnidipine attenuated 3-week AF effects on AF duration and atrial conduction, and suppressed AF-induced increases in fibrous-tissue content, decreases in connexin-43 expression and reductions in sodium-channel expression. CONCLUSIONS:Cilnidipine, a commercially available NTCC-blocking drug, prevents AF-induced autonomic, electrical and structural remodelling, along with associated AF promotion.

Project description:Introduction: Atrial fibrillation (AF) is the most common arrhythmia and affects around 1% of the population with increasing incidence and substantial morbidity. Functional effects of genetic variants associated with AF should help to identify targets involved in AF initiation and/or subsequent remodeling. Gene variants next to the gene of the transcription factor PITX2 (paired-like homeodomain transcription factor 2) showed the strongest association with AF. A significant number of AF patients showed reduced PITX2 levels in the left atrium. Mouse models have been used to study functional aspects of PITX2 gene deletion (“knock out”), but there are substantial differences in atrial electrophysiology between mouse and human . HiPSC-CM should be able to bridge the gap, provided the cells reproduce typical characteristics of human atrium. Methods: PITX2 knock out samples from a control cell line of human induced pluripotent stem cells (hiPSC) were obtained. Differentiation and generation of Atrial-like engineered heart tissue (aEHT) was performed. RNA-sequencing (RNA-Seq), Quantitative Real-time PCR (RT-qPCR), Protein analysis by Western Blot, Contraction and force analysis, action potential measurements, Calcium current measurements and differential gene expression analysis were run on the samples. Results: Effective knock out of PITX2 was confirmed by mRNA sequencing and WB. It was shown that PITX2 deficiency reduces contraction force. PITX2 deficiency induces action potential triangulation with more negative maximum diastolic potential. Activation of muscarinic receptors shortens APD in both PITX2 knockout and controls but hyperpolarization is lost in PITX2 knock out. It was shown that Ca2+ current density is smaller in PITX2 knock out than controls. We found that more negative MDP in PITX2 knock out is not associated with higher IK1. Conclusion: We improved atrial differentiation, coming very close to human atrial electrophysiology. We demonstrate that PITX2 deficiency induces key characteristics known from persistent AF.

Project description:Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.

Dataset Information

Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel.

Publications

Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel.

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