A combined molecular and electrophysiological approach to understand the effect of interleukin 6 in cardiac myocytes
Cardiovascular Research
; 118:i19, 2022.
Article
in English
| EMBASE | ID: covidwho-1956561
ABSTRACT
Background and purpose:
Increased inflammatory cytokines, including interleukin 6 (IL-6), are associated to enhanced arrhythmogenic risk, including atrial fibrillation [1]. Moreover, direct effects of cytokines on ion channels are emerging as important mediators of arrhythmogenic remodeling [2]. In line with this, enhanced arrhythmogenesis in COVID-19 patients is hypothesized to be driven by cytokine storms, a well demonstrated condition in this setting [3]. To dissect the underlying mechanisms explaining such an association, we evaluated the proarrhythmogenic alterations of IL-6, assessing the impact on the expression of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, of the regulatory subunits MiRP1, and on the action potential (AP) profile in HL-1 cardiomyocytes (CMs). In human left atrial samples we studied the relation occurring between the expression levels of IL-6 and of HCN channels. In human induced pluripotent stem cell (hiPSC)-derived CMs we evaluated the acute effects of IL-6 on pacemaker activity.Methods:
HL-1 CMs exposed to 50 ng/ml IL-6 or vehicle were collected after 0, 0.5, 6, 12, 24 and 48 h to study intracellular signaling, ion channel expression and AP profile. The latter was assessed through a high-throughput system allowing optical detection of APs with optical stimulation. In human atrial samples obtained from patients undergoing surgery, IL-6 and HCN mRNA expression were analyzed by quantitative RT-PCR. The acute effects on pacemaker activity were evaluated in hiPSC-derived CMs exposed to increasing concentrations of IL-6.Results:
In HL1 CMs IL-6 rapidly induces STAT3 phosphorylation, demonstrating the activation of IL-6 signaling cascade. IL-6 modifies HCN channel transcript and proteins at different time points, evidencing a significant downregulation of HCN4 isoform and significant upregulations of HCN1, HCN2 and MiRP1. In line with this, in human left atrial samples, expression levels of IL-6 were linearly and directly related to HCN1 channel, while they were linearly and inversely related to HCN4. Electrophysiological recordings on HL-1 CMs showed a decreasing trend of AP amplitude and of maximum diastolic potential, while AP durations tended to increase. In hiPSC-derived CMs IL-6 reduces the frequency of AP in a concentration-dependent manner.Conclusions:
Our data demonstrate that in HL-1 CMs IL-6 activates a STAT3 dependent intracellular signaling that is associated to subsequent variation of HCN channel expression and a concurrent alteration of AP profile. The relation between IL-6 and HCN1,4 expression in human samples suggests a mechanistic link between IL-6 levels and ionic channel targets, including HCN channels. The reduction of AP frequency in hiPSC-derived CMs suggests a direct interaction with ion channels. We hypothesize that these modifications may lay the basis to enhance the propensity of atria to develop arrhythmias in condition of elevate IL-6 levels.
cyclic nucleotide; endogenous compound; hyperpolarization activated cyclic nucleotide gated channel; interleukin 6; messenger RNA; potassium channel KCNE2; STAT3 protein; action potential; action potential amplitude; action potential duration; adult; cardiac muscle cell; cardiac rhythm management device; conference abstract; controlled study; down regulation; electrophysiological procedures; gene expression; gene frequency; genetic transcription; heart arrhythmia; heart left atrium; HL-1 cell line; human; human cell; human tissue; hyperpolarization; IL 6 signaling; induced pluripotent stem cell; intracellular signaling; maximum diastolic potential; protein expression; protein function; protein phosphorylation; quantitative analysis; real time polymerase chain reaction; signal transduction; upregulation
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Type of study:
Experimental Studies
Language:
English
Journal:
Cardiovascular Research
Year:
2022
Document Type:
Article
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