Lipopolysaccharides Up-regulate Kir6.1/SUR2B Channel Expression and Enhance Vascular KATP Channel Activity via NF-κB-dependent Signaling

Shi, Weiwei; Cui, Ningren; Wu, Zhongying; Yang, Yang; Zhang, Shuang; Gai, Hongyu; Zhu, Daling; Jiang, Chun

doi:10.1074/jbc.m109.058313

Cited by 41 publications

(39 citation statements)

References 36 publications

(47 reference statements)

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“…Electrophysiology-Patch clamp experiments were performed according to our previous reports (13)(14)(15)(16)(17)(18). Whole-cell currents were recorded in voltage clamp with a holding potential of 0 mV and a hyperpolarizing step to Ϫ80 mV.…”

Section: Methodsmentioning

confidence: 99%

Molecular Basis and Structural Insight of Vascular KATP Channel Gating by S-Glutathionylation

Yang

Shi

Chen

et al. 2011

Journal of Biological Chemistry

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had only a modest contribution to S-glutathionylation, and Cys 120 was modulated by extracellular oxidants but not intracellular GSSG. Simulation modeling of Kir6.1 S-glutathionylation suggested that after incorporation to residue 176, the GSH moiety occupied a space between the slide helix and two transmembrane helices. This prevented the inner transmembrane helix from undergoing conformational changes necessary for channel gating, retaining the channel in its closed state. ATP-sensitive Kϩ (K ATP ) 7 channels are expressed in a variety of tissues, including smooth muscles, pancreatic ␤-cells, myocardium, and neurons, where they play an important role in cellular function (1, 2). Activity of the K ATP channels is tuned by physiological or pathophysiological stimuli, including hypoxia, hyperglycemia, ischemia, and oxidative stress, allowing a regulation of cellular excitability according to the metabolic state (3). The vascular smooth muscle (VSM) isoform of K ATP channels regulates vascular tones (4, 5). Activation of the channel by vasodilators produces hyperpolarization of VSM cells, reduces activity of the voltage-dependent Ca 2ϩ channels, and relaxes VSMs. Inhibition of the channel leads to constriction of VSMs. Disruption of the vascular K ATP channel in mice results in vasospasm in coronary arteries and sudden cardiac death (6, 7).Other studies have further shown that disruption of the vascular K ATP channel has drastic effects on the systemic response to septic stress. With a forward genetic approach by genomewide random chemical mutagenesis, Croker et al. (8) screened a large population of mice and found four strains that are highly susceptible to multiple septic pathogens, including lipopolysaccharides (LPSs). The LPS hypersensitivity phenotype of these mice is due to a null allele of Kcnj8, encoding the Kir6.1 subunit of the vascular K ATP channel (8). Similar septic susceptibility has been observed in Kcnj8-knock-out mice that also show coronary hypoperfusion and myocardial ischemia during LPS exposure (9). These studies thus indicate that the vascular K ATP channel not only contributes to the vascular tone regulation at physiological conditions but also affects critically systemic stress responses.Our recent studies have shown that the vascular K ATP channel is strongly inhibited in oxidative stress by S-glutathionylation (10). S-Glutathionylation is a post-translational modification mechanism occurring in a variety of physiological or pathophysiological conditions (11). This protein modulation mechanism is remarkable especially in vasculatures because oxidative stress is a major contributing factor to several cardiovascular diseases, in which S-glutathionylation plays an important role (12). Although S-glutathionylation is often associated with the adverse effects of oxidative stress, such a protein modulation is reversible under certain circumstances and can act as a functional modulation mechanism like protein phosphorylation (11). Thus, demonstration of how S-glutathionylation * This work was s...

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Section: Methodsmentioning

confidence: 99%

Molecular Basis and Structural Insight of Vascular KATP Channel Gating by S-Glutathionylation

Yang

Shi

Chen

et al. 2011

Journal of Biological Chemistry

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“…Bacterial endotoxins, such as lipopolysaccharide (LPS), have previously been shown to induce excessive activation and up regulation of vascular K ATP channels, to induce hypotension and to substantially reduce vascular sensitivity to vasoconstrictive agents [26,27]. H 2 S has been proposed as a potential endogenous ligand for K ATP channels and induces K ATP channel-mediated vasorelaxation [28] in several vascular tissues, promoting speculation that H 2 S may play a role in endotoxic shock, an important form of acute inflammation, as mentioned.…”

Section: H 2 S and Acute Whole-body Inflammation (Sepsis)mentioning

confidence: 99%

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

Whiteman

Winyard

2011

Expert Review of Clinical Pharmacology

277

232

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“…In an experimental colitis animal model, the activities and gene expression of K ATP are increased in colonic myocytes [23]. It has been reported that LPS increased the activity and gene expression of K ATP channels in vascular tissue and cells [24,25]. Previously, we found that H 2 O 2 , an inflammatory mediator, suppresses pacemaker activities by the activation of K ATP channels in mouse in- testinal ICCs [26].…”

Section: Discussionmentioning

confidence: 99%

Action of Lipopolysaccharide on Interstitial Cells of Cajal from Mouse Small Intestine

et al. 2012

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Background and Purpose: Lipopolysaccharide (LPS) induces intestinal dysmotility by alteration of smooth muscle and enteric neuronal activities. However, there is no report on the modulatory effects of LPS on the interstitial cells of Cajal (ICCs). We investigated the effect of LPS and its signal transduction in ICCs. Methods: We performed whole-cell patch clamp and RT-PCR in cultured ICCs from mouse small intestine. Results: LPS suppressed the generation of pacemaker currents of ICCs. The mRNA transcripts for Toll-like receptor 4 (TLR4) were expressed in ICCs. However, the inhibitory action of LPS on pacemaker currents from TLR4^+/+ mice was not present in TLR4^–/– mice. The inhibitory effects of LPS on ICCs were blocked by glibenclamide (an inhibitor of ATP-sensitive K⁺ channels), NS-398 (a COX-2 inhibitor), AH6808 [a prostaglandin E₂ (PGE₂)-EP₂ receptor antagonist], ODQ (an inhibitor of guanylate cyclase) and L-NAME [an inhibitor of nitric oxide synthase (NOS)]. Furthermore, genistein and herbimycin A (tyrosine kinase inhibitors) blocked the LPS-induced inhibitory action on pacemaker activity in ICCs. Conclusions: LPS can activate ICCs to release NO and PGE₂ through TLR4 activation. The released NO and PGE₂ inhibit pacemaker currents by activating ATP-sensitive K⁺ channels. The LPS actions are mediated by tyrosine kinase signaling pathways.

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Lipopolysaccharides Up-regulate Kir6.1/SUR2B Channel Expression and Enhance Vascular KATP Channel Activity via NF-κB-dependent Signaling

Cited by 41 publications

References 36 publications

Molecular Basis and Structural Insight of Vascular KATP Channel Gating by S-Glutathionylation

Molecular Basis and Structural Insight of Vascular KATP Channel Gating by S-Glutathionylation

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

Action of Lipopolysaccharide on Interstitial Cells of Cajal from Mouse Small Intestine

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