Toll-like receptor 4–induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca2+ leakage promote cardiac contractile dysfunction in sepsis

Abstract

Studies suggest the potential role of a sarcoplasmic reticulum (SR) Ca leak in cardiac contractile dysfunction in sepsis. However, direct supporting evidence is lacking, and the mechanisms underlying this SR leak are poorly understood. Here, we investigated the changes in cardiac Ca handling and contraction in LPS-treated rat cardiomyocytes and a mouse model of polymicrobial sepsis produced by cecal ligation and puncture (CLP). LPS decreased the systolic Ca transient and myocyte contraction as well as SR Ca content. Meanwhile, LPS increased Ca spark-mediated SR Ca leak. Preventing the SR leak with ryanodine receptor (RyR) blocker tetracaine restored SR load and increased myocyte contraction. Similar alterations in Ca handling were observed in cardiomyocytes from CLP mice. Treatment with JTV-519, an anti-SR leak drug, restored Ca handling and improved cardiac function. In the LPS-treated cardiomyocytes, mitochondrial reactive oxygen species and oxidative stress in RyR2 were increased, whereas the levels of the RyR2-associated FK506-binding protein 1B (FKBP12.6) were decreased. The Toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 reduced the oxidative stress in LPS-treated cells, decreased the SR leak, and normalized Ca handling and myocyte contraction. Consistently, TLR4 deletion significantly improved cardiac function and corrected abnormal Ca handling in the CLP mice. This study provides evidence for the critical role of the SR Ca leak in the development of septic cardiomyopathy and highlights the therapeutic potential of JTV-519 by preventing SR leak. Furthermore, it reveals that TLR4 activation-induced mitochondrial reactive oxygen species production and the resulting oxidative stress in RyR2 contribute to the SR Ca leak.

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

“…15 A recent study showed that TLR4 activation induced Ca 2+ leakage via regulating FKBP12.6 dissociation from RyR2 in septic cardiomyocytes. 45 Thus, we hypothesized that DEX may attenuate myocardial I/R injury by inhibiting [Ca 2+ ]i overload via TLR4-mediated FKBP12.6/RyR2 signaling pathway. In addition to the action on α2 adrenergic receptors, DEX may act on ion channels and membrane potential.…”

Current Status of Septic Cardiomyopathy: Basic Science and Clinical Progress

“…A study has shown beneficial effect of TLR4 inhibitor (TAK-242) through preventing SR Ca 2+ leak in septic mice. Coincidentally, TLR4 deficiency significantly improved cardiac function and corrected abnormal Ca 2+ handling in septic mice (Yang et al, 2018), which indicate that the critical role of TLR4-dependent SR Ca 2+ leak in the development of SCM.…”

“…The linkage between activations of TLRs/its downstream signals and SCM has been established from current investigations. Inhibition of TLR4 has shown protective effect on SCM in experimental animal models (Fenhammar et al, 2014;Yang et al, 2018). Based on those findings, targeting TLRs to develop new therapeutic approaches is promising.…”

“…TLR4 can bind to LPS, and then cause the release of a variety of inflammatory factors, finally insults in cardiac dysfunction (Vallejo, 2011). TLR4 regulates oxidative stress in ryanodine receptor 2 (RyR2), leading to increased Ca 2+ leakage in the sarcoplasmic reticulum (SR) of cardiac myocytes (Yang et al, 2018). Chen et al (2019b) analyzed gene expression in septic patients compared with control, showing that TNF-α, JAK and transcriptional activation (STAT) signaling pathways were up-regulated.…”

The Antiemetic Effect of Xiao-Ban-Xia-Tang Formula is Associated With Regulating CaM/CaMKII/ERK1/2 Signaling Pathway in Cisplatin and 1-phenylbiguanide Hydrochloride Induced Rat Pica Models

“…Ca 2+ plays an important role in stimulus-response reactions of cells as a second messenger, which involves in several elements, such as LTCC, mitochondria, transient receptor potential channel and ryanodine receptor [51][52][53][54]. In present study, we focused on the effects of XBXT on CaM/CaMKII/ERK1/2 signaling pathway.…”