Abstract
Sepsis, an inflammatory response to infection provoked by lipopolysaccharide (LPS), is associated with high mortality, as well as ischemic stroke and new-onset atrial arrhythmia. Severe bacterial infections causing sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction and finally death. LPS challenge-induced inflammatory responses during sepsis may increase the likelihood of the arrhythmogenesis. Lemnalol is known to possess potent anti-inflammatory effects. This study examined whether Lemnalol (0.1 μM) could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes under the influence of LPS (1μg/mL). Under challenge with LPS, Lemnalol-treated LA myocytes, had a longer AP duration at 20%, 50% and 90% repolarization of the amplitude, compared to the LPS-treated cells. LPS-challenged LA myocytes showed increased late sodium current, Na+-Ca2+ exchanger current, transient outward current, rapid component of delayed rectifier potassium current, tumor necrosis factor-α, NF-κB and increased phosphorylation of ryanodine receptor (RyR), but a lower L-type Ca2+ current than the control LA myocytes. Exposure to Lemnalol reversed the LPS-induced effects. The LPS-treated and control groups of LA myocytes, with or without the existence of Lemnalol. showed no apparent alterations in the sodium current amplitude or Cav1.2 expression. The expression of sarcoendoplasmic reticulum calcium transport ATPase (SERCA2) was reduced by LPS treatment, while Lemnalol ameliorated the LPS-induced alterations. The phosphorylation of RyR was enhanced by LPS treatment, while Lemnalol attenuated the LPS-induced alterations. In conclusion, Lemnalol modulates LPS-induced alterations of LA calcium homeostasis and blocks the NF-κB pathways, which may contribute to the attenuation of LPS-induced arrhythmogenesis.
Highlights
The most prevalent arrhythmia in the clinical is atrial fibrillation (AF) [1]
Tumor necrosis factor-α (TNF-α), platelet-activating factor (PAF), interleukin (IL)-1β, IL-6, IL-8, IL-10 and chemokines produce an inflammatory effect upon adjacent cardiac tissues [6,7,8]
There was a significant difference in action potential duration (APD); there were similarities in the AP amplitude (APA) and resting membrane potential among the control, LPS, and LPS + Lemnalol groups
Summary
The occurrence of AF is closely associated with the interaction of cardiac tissues and the inflammatory response, including a variety of immune proteins and the cells they mediate. Severe bacterial infections always result in profound physiological alterations, including high fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ failure and death. Macrophages activated by lipopolysaccharides (LPS) secrete many inflammatory mediators [5]. Inflammatory mediators and activated immune cells work together to cause clinical symptoms, such as arrhythmogenesis, peripheral vascular dilation, thrombogenesis, endothelial damage and fever [9]. LPS was shown to cause marked increases in systemic inflammatory responses via the nuclear factor NF–κB signaling pathway and associated biochemical and physiological regulation [12,13]
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