The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most frequent arrhythmia in adults. The prevalence and incidence of AF is going to increase substantially over the next few decades. Because AF increases the risk of stroke, heart failure, dementia, and others, it severely impacts the quality of life, morbidity, and mortality. Although the pathogenesis of AF is multifaceted and complex, focal ectopic activity and reentry are considered as the fundamental proarrhythmic mechanisms underlying AF development. Over the past 2 decades, large amount of evidence points to the key role of intracellular Ca²⁺ dysregulation in both initiation and maintenance of AF. More recently, emerging evidence reveal that NLRP3 (NACHT, LRR, PYD domain-containing 3) inflammasome pathway contributes to the substrate of both triggered activity and reentry, ultimately promoting AF. In this article, we review the current state of knowledge on Ca²⁺ signaling and NLRP3 inflammasome activity in AF. We also discuss the potential crosstalk between these two quintessential contributors to AF promotion.

Keywords: Atrial fibrillation; Calcium; Delayed afterdepolarization; NLRP3 inflammasome; Ryanodine receptor type-2; SERCA; Sodium-calcium exchanger.

Figure 1.. Putative molecular mechanisms contributing to abnormal Ca²⁺ handling associated with atrial fibrillation (AF).

Focal ectopic firing due to the delayed afterdepolarization (DAD)-induced triggered activity (TA), APD shortening, and atrial enlargement as a result of the upregulation of hypertrophic and profibrogenic genes are key events associated with dysregulated Ca²⁺ handling in atrial cardiomyocytes during AF. DAD-inducing sarcoplasmic reticulum (SR) Ca²⁺ release (SR Ca²⁺ leak) is higher due to the enhanced activity of ryanodine receptor type-2 (RyR2). The latter could be a consequence of an impaired interaction with FKBP (FK506-binding protein 12.6) or junctophilin-2 (JPH2), altered phosphorylation by CaMKII, PKA, and SPEG, or a combination of both. The SERCA2a-mediated SR Ca²⁺ uptake could be increased in pAF because of a reduction of sarcolipin (SLN) or a hyperphosphorylation of phospholamban (PLB). In cAF, the hyperphosphorylation of PLB is associated with the enhanced Inhibitor-I (I-1) mediated inhibition of protein phosphatase type-1 (PP1). These alterations lead to the enhanced SR Ca²⁺ leak, which can activate the Na⁺/Ca²⁺ exchanger 1 (NCX1) and promote DADs. The shortening of APD is partially due to the reduced level of Cav1.2 (α-subunit of L-type Ca²⁺ channel, LTCC) or increased LTCC dephosphorylation due to enhanced activity of PP1 and PP2A. Together with structural remodeling involving Ca²⁺-induced calcineurin (CaN)-mediated activation of NFAT (nuclear factor of activated T-cell), a transcription factor associated with the hypertrophy and fibrosis, AP shortening promote AF-maintaining reentry.

Figure 2.. Potential mechanisms underlying NLRP3 inflammasome activation.

Activation of NLRP3 involves two major processes: priming and triggering. Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) activate toll-like receptor (TLR), and subsequently induce NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)-mediated transcription of inflammasome components (NLRP3, ASC, and pro-Caspase-1) and effectors (pro-IL-1β and pro-IL-18). A wide array of triggering signals may promote the inflammasome assembly. To date, the most established triggering stimuli include 1) K⁺ efflux via the purinergic receptor P2X7R, 2) increased intracellular Ca²⁺ levels, 3) ER stress, 4) enhanced cathepsin-B release by lysosome rapture, and 5) increased ROS generation. Spatial arrangement organized by the microtubule network is also essential for the inflammasome assembly. The activation of inflammasome promotes the autocleavage of caspase-1. Mature caspase-1 activates IL-1β, IL-18, and gasdermin-D (GSDMD). N-fragmented GSDMD (Nt-GSDMD) creates membrane pores and facilitate the release of mature IL-1β and IL-18.

Figure 3.. Crosstalk signaling between altered Ca²⁺ handling and NLRP3 inflammasome signaling in atrial fibrillation (AF).

The increase in sarcoplasmic reticulum (SR) Ca²⁺ release (SR Ca²⁺ leak) in cardiomyocytes may directly activate the NLRP3 inflammasome by facilitating the inter-domain interactions between inflammasome components or may have indirect effects by promoting the mitochondria (mito)-derived ROS production. Increased levels of ROS due to the enhanced function of mitochondria or NADPH oxidase type-2 (NOX2) can activate CaMKII and RyR2, perpetuating the Ca²⁺-induced activation of the inflammasome. Abnormal Ca²⁺ signaling might also trigger the HDAC6-mediated inflammasome activation. Conversely, the enhancement of the NLRP3 inflammasome could amplify the CaMKII-mediated augmentation in SR Ca²⁺ handling via abnormal IL-1β signaling or elevate RyR2 protein level and RyR2-mediated Ca²⁺ release via IL-1β or caspase-1 independent mechanisms. Solid lines indicate established regulation patterns, dash lines indicate putative mechanisms that require direct demonstration.