Alterations in the expression of atrial calpains in electrical and structural remodeling during aging and atrial fibrillation

Xu, Guoqing; Gan, Tianyi; Tang, Baopeng; Chen, Zu-Heng; Mahemuti, Ailiman; Jiang, Tao; Song, Jianguo; Guo, Xia; Li, Yaodong; Zhou, Xianhui; Zhang, Yu; Li, Jinxin

doi:10.3892/mmr.2013.1684

Cited by 13 publications

(12 citation statements)

References 32 publications

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“…Previous studies have shown that activated calpain mediated the degradation of myofibrillar structure [27], cardiomyocyte loss [28] and I Ca, L reduction [29] in the pressure-overloaded feline myocardium and atrial fibrillation models. Given our results showing structural and electrical remodelling in the paced VCMs, we hypothesized that the inhibition of calpain may attenuate the adverse effects of pacing.…”

Section: Resultsmentioning

confidence: 99%

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Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes

et al. 2017

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BackgroundLong-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro.MethodsHuman induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing.ResultsCompared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the ICa, L in paced VCMs.ConclusionsThe results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0566-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…Considering that activated calpain mediated the degradation of myofibrillar structure [27], cardiomyocyte loss [28] and I Ca, L reduction [29], we hypothesized that the inhibition of calpain may attenuate the adverse effects of pacing. Cardiac troponin T was reported to be a marker of cardiomyocytes [46].…”

Section: Discussionmentioning

confidence: 99%

Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes

et al. 2017

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“…Other ECM macromolecules (i.e., glycoproteins, proteoglycans) are, at this time, degraded by neutral protease activity [83]. However, protocols using a primary digestion with protease, only later employing collagenase have been described [84], as have protocols using collagenase alone [85,86].…”

Section: Enzymatic Digestionmentioning

confidence: 97%

Methods for isolating atrial cells from large mammals and humans

Voigt

Pearman²,

Dobrev

et al. 2015

Journal of Molecular and Cellular Cardiology

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The identification of disturbances in the cellular structure, electrophysiology and calcium handling of atrial cardiomyocytes is crucial to the understanding of common pathologies such as atrial fibrillation. Human right atrial specimens can be obtained during routine cardiac surgery and may be used for isolation of atrial myocytes. These samples provide the unique opportunity to directly investigate the effects of human disease on atrial myocytes. However, atrial myocytes vary greatly between patients, there is little if any access to truly healthy controls and the challenges associated with assessing the in vivo effects of drugs or devices in man are considerable. These issues highlight the need for animal models. Large mammalian models are particularly suitable for this purpose as their cardiac structure and electrophysiology are comparable with humans. Here, we review techniques for obtaining atrial cardiomyocytes. We start with background information on solution composition. Agents shown to increase viable cell yield will then be explored followed by a discussion of the use of tissue-dissociating enzymes. Protocols are detailed for the perfusion method of cell isolation in large mammals and the chunk digest methods of cell isolation in humans.

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“…Changes in atrial electrophysiology and structure, referred to as remodeling, constitute the primary features of AF occurrence, maintenance and recurrence (6,7). Changes in ion currents, including Ca 2+ and K + , form the basis for early electrical remodeling in AF (8,9).…”

Section: Introductionmentioning

confidence: 99%

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

Wang

Zhu

et al. 2016

Molecular Medicine Reports

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Remodeling of atrial electrophysiology and structure is the primary feature of atrial fibrillation (AF). Evidence suggests that abnormalities in the expression levels of embryological cardiovascular development‑associated transcription factors, including Nkx2.5, are crucial for the development of AF. Rat atrial myocardial cells (AMCs) in culture dishes were placed in an electric field and stimulated. Transmission electron microscopy was used to observe the ultrastucture prior to and following rapid pacing. The action potential durations and effective refractory periods were measured. RT‑PCR and western blotting were performed to investigate the effect of rapid pacing on the expression levels of ion channel and nuclear proteins in AMCs. Nkx2.5 short interfering RNA (siRNA) transfection was performed. Through this in vitro rat AMC culture and rapid pacing model, it was demonstrated that rapid pacing shortened the action potential and downregulated the expression levels of L‑type calcium and potassium channels. Expression levels of Nkx2.5 and cardiac ankyrin repeat protein (CARP) were significantly upregulated by rapid pacing at the mRNA and protein levels. siRNA‑mediated Nkx2.5 silencing attenuated the rapid pacing‑induced downreglation of ion channel levels. These results suggest that the Nkx2.5/CARP signaling pathway contributes to the early electrical remodeling process of AF.

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Alterations in the expression of atrial calpains in electrical and structural remodeling during aging and atrial fibrillation

Cited by 13 publications

References 32 publications

Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes

Structural and electrophysiological dysfunctions due to increased endoplasmic reticulum stress in a long-term pacing model using human induced pluripotent stem cell-derived ventricular cardiomyocytes

Methods for isolating atrial cells from large mammals and humans

Nkx2.5/CARP signaling pathway contributes to the regulation of ion channel remodeling induced by rapid pacing in rat atrial myocytes

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