Arrhythmogenic and chronotropic effects of bronchodilator drugs on human cardiomyocytes

Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated.

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AIM2-driven inflammasome activation in chronic heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.0847 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Ruppert ◽

Z.S Onodi ◽

P Leszek ◽

V.E Toth ◽

G Koncsos ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Animal Models ◽

Left Ventricular ◽

Inflammasome Activation ◽

Coronary Artery Ligation ◽

Funding Source ◽

Human Cardiomyocytes ◽

Pannexin 1 ◽

End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

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Inhibition of rat ventricular automaticity by adenosine

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1985.248.6.h907 ◽

1985 ◽

Vol 248 (6) ◽

pp. H907-H913 ◽

Cited By ~ 2

Author(s):

L. J. Heller ◽

R. A. Olsson

Keyword(s):

Cell Surface ◽

Cell Surface Receptor ◽

Chronotropic Effect ◽

Surface Receptors ◽

Adenosine Concentration ◽

Surface Receptor ◽

Ventricular Automaticity ◽

Beating Rate ◽

Chronotropic Effects ◽

Developed Pressure

This study was designed to characterize adenosine's negative chronotropic effect on ventricular pacemakers. The spontaneous beating rate of isolated, isovolumic rat ventricular preparations perfused with Krebs-Henseleit solution decreased as the adenosine concentration was increased [log M effective concentration 50% (EC50) = -5.22 +/- 0.17]. The lack of effect of propranolol or atropine on this adenosine response eliminates the involvement of endogenous neurotransmitters. Support for the involvement of an external cell surface receptor was provided by findings that theophylline and 8-(4-sulfophenyl)theophylline, an analogue thought to act solely at the cell surface, significantly increased the adenosine log M EC50 to -3.94 +/- 0.22 and -3.61 +/- 0.22, respectively. An increase in spontaneous beating rate induced by theophylline, but not by its analogue, was blocked by the addition of propranolol. The relative chronotropic potency of the adenosine analogues R-PIA, S-PIA, and NECA suggests that the cell surface receptors may be of the Ri type. The negative chronotropic effects of adenosine and its analogues occurred at concentrations that had no effect on the developed pressure of the paced preparation. Electrocardiographic evaluations indicate that at high agonist concentrations, there was an abrupt alteration in electrical properties of the preparation, which could be blocked by theophylline and its analogue.

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Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa154 ◽

2020 ◽

Author(s):

Kang Zhou ◽

Yan Xu ◽

Qiong Wang ◽

Lini Dong

Keyword(s):

Cell Viability ◽

Cell Apoptosis ◽

Myocardial Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Damage ◽

Protective Role ◽

Human Cardiomyocytes ◽

Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

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