Cold-Inducible RNA-Binding Protein Regulates Cardiac Repolarization by Targeting Transient Outward Potassium Channels

Li, Jun; Xie, Duanyang; Huang, Jian; Lv, Fei; Shi, Dan; Liu, Yi; Lin, Li; Li, Geng; Wu, Yangjun; Liang, Dandan; Chen, Yi Han

doi:10.1161/circresaha.116.306287

Cited by 46 publications

(32 citation statements)

References 14 publications

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“…In this early-stage CKD model, we demonstrated that the overall electrocardiographic QTc was prolonged in CKD rats compared to sham-operated rats; this prolongation was mediated by an extensive lengthening of APD in EPI cardiomyocytes compared with ENDO cardiomyocytes and was secondary to a substantial reduction of I to in the EPI region. The finding that modulation of I to leads to prolongation or abbreviation of APD was concordant with the observation by Li et al 24,. who showed that ablation of cold-inducible, RNA-binding protein–mediated I to amplification shortened the QTc interval in rats.…”

Section: Discussionsupporting

confidence: 92%

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

Lee

Chen

Chan

et al. 2017

Sci Rep

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The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.

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Section: Discussionsupporting

confidence: 92%

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

Lee

Chen

Chan

et al. 2017

Sci Rep

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“…Ventricular myocytes were isolated from 12-week-old WT and KI mice using a previously described method 23. Isolated cardiomyocytes were applied for recording Na + current and action potential (AP) by whole-cell patch clamping at room temperature as previously described 23 24.…”

Section: Methodsmentioning

confidence: 99%

Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density

Cheng

Han

et al. 2017

J Med Genet

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“…iCIRP is synthesized in the cytoplasm and gets back into the nucleus to modulate homeostatic RNA transcription and processing . In cardiomyocytes, for example, iCIRP regulates cardiac repolarization by binding to and inhibits the translation of mRNAs encoding Ito channel proteins . However, a fraction of iCIRP can also be found in the cytoplasm.…”

Section: Intracellular Cirp An Rna Chaperonementioning

confidence: 99%

Extracellular CIRP (eCIRP) and inflammation

Aziz

Brenner

Wang

2019

Journal of Leukocyte Biology

159

188

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Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of intracellular CIRP (iCIRP) as a stress-response protein has been extensively studied. Recently, extracellular CIRP (eCIRP) was discovered to also have an important role, acting as a damage-associated molecular pattern, raising critical implications for the pathobiology of inflammatory diseases. During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-B and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors. Studies with CIRP −/− mice reveal protection against inflammation, implicating eCIRP to be a novel drug target. Anti-CIRP Ab or CIRP-derived small peptide may have effective therapeutic potentials in sepsis, acute lung injury, and organ ischemia/reperfusion injuries. The current review focuses on the pathobiology of eCIRP by emphasizing on signal transduction machineries, leading to discovering novel therapeutic interventions targeting eCIRP in various inflammatory diseases. K E Y W O R D S ALI, CIRP, DAMP, eCIRP, hemorrhage, inflammation, ischemia/reperfusion, macrophage, neutrophils, sepsis PMN, polymorphonuclear neutrophils; RA, rheumatoid arthritis; RM, reverse migrated; rTEM, reverse transendothelial migration; STAT3, signal transducer and activator of transcription 3; TRPV, transient receptor potential vanilloid; UC, ulcerative colitis telomerase maintenance, 7 stress adaptation, 8 and tumor formation and progression. 9,10 These iCIRP activities, which allow cells to cope with various cellular stress conditions, have been reviewed in detail. 8 In contrast to iCIRP, extracellular CIRP (eCIRP) was recently discovered to act as a damage-associated molecular pattern (DAMP) promoting inflammation and injury. 11 The identification of eCIRP as a new DAMP has originated a new era of investigation in inflammation pathobiology. Serum levels of eCIRP not only were found to be elevated in individuals admitted to the intensive care unit (ICU)with hemorrhagic shock (HS), but also correlated with organ injury. 11 Furthermore, it was demonstrated that eCIRP was able to promote inflammation independently. 11 In cells subjected to hypoxia, CIRP translocates from its usual location in the nucleus to the cytosol 1,12 and is then released to the extracellular space. 11 eCIRP then acts as a DAMP increasing macrophage production of proinflammatory cytokines. 11 Since its original discovery as a DAMP, eCIRP's emerging proinflammatory role has been progressively extended to include additional target cells, such as neutrophils, lymphocytes, epithelial cells, and endothelial cells. 13-2...

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Cold-Inducible RNA-Binding Protein Regulates Cardiac Repolarization by Targeting Transient Outward Potassium Channels

Cited by 46 publications

References 14 publications

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density

Extracellular CIRP (eCIRP) and inflammation

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