Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation

Park, Sang Woong; Noh, Hyun Ju; Sung, Dong Jun; Kim, Jae Gon; Kim, Jeong‐Min; Ryu, Shin-Young; Kang, Kook Hee; Kim, Bokyung; Bae, Young Min; Cho, Hana

doi:10.1007/s00424-014-1513-3

Cited by 47 publications

(40 citation statements)

References 80 publications

(104 reference statements)

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“…The remaining TRPV1-independent H 2 O 2 -mediated relaxation may be due to the compensatory mechanisms in V1KO mice such as KV channels (as indicated by 4-AP-mediated suppression of H 2 O 2 -mediated relaxation in V1KO mice). Indeed, we found that blocking KV channels with 4-AP together with SB366791 completely abolished H 2 O 2 -induced vasodilation, consistent with previous studies on KV channels, [2, 42, 47, 48]—reinforcing a role for TRPV1. BK Ca channels have been shown to contribute to arterial tone[33], however, unlike BK Ca -dependent H 2 O 2 -induced dilation in previous studies [3, 64], the BK Ca channel did not contribute significantly to the dilatory effect in our study, suggesting that the H 2 O 2 -dependent sensitivity of K + channels differs among vascular beds and perhaps species.…”

Section: Discussionsupporting

confidence: 91%

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

et al. 2016

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We demonstrated previously that TRPV1-dependent coupling of coronary blood flow (CBF) to metabolism is disrupted in diabetes. A critical amount of H2O2 contributes to CBF regulation; however, excessive H2O2 impairs responses. We sought to determine the extent to which differential regulation of TRPV1 by H2O2 modulates CBF and vascular reactivity in diabetes. We used contrast echocardiography to study TRPV1 knockout (V1KO), db/db diabetic, and wild type C57BKS/J (WT) mice. H2O2 dose-dependently increased CBF in WT mice, a response blocked by the TRPV1 antagonist SB366791. H2O2-induced vasodilation was significantly inhibited in db/db and V1KO mice. H2O2 caused robust SB366791-sensitive dilation in WT coronary microvessels; however, this response was attenuated in vessels from db/db and V1KO mice, suggesting H2O2-induced vasodilation occurs, in part, via TRPV1. Acute H2O2 exposure potentiated capsaicin-induced CBF responses and capsaicin-mediated vasodilation in WT mice, whereas prolonged luminal H2O2 exposure blunted capsaicin-induced vasodilation. Electrophysiology studies re-confirms acute H2O2 exposure activated TRPV1 in HEK293A and bovine aortic endothelial cells while establishing that H2O2 potentiate capsaicin-activated TRPV1 currents, whereas prolonged H2O2 exposure attenuated TRPV1 currents. Verification of H2O2-mediated activation of intrinsic TRPV1 specific currents were found in isolated mouse coronary endothelial cells from WT mice and decreased in endothelial cells from V1KO mice. These data suggest prolonged H2O2 exposure impairs TRPV1-dependent coronary vascular signaling. This may contribute to microvascular dysfunction and tissue perfusion deficits characteristic of diabetes.

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Section: Discussionsupporting

confidence: 91%

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

et al. 2016

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“…36 H 2 O 2 also activates smooth muscle K V 2.1 channels in rat mesenteric arteries through a similar mechanism via S-glutathionylation. 13 It remains to be determined whether H 2 O 2 -induced dilation involves redox modification of K V channels, or alternatively other intermediate signaling proteins as we reported previously for protein kinase G in H 2 O 2 -induced BK Ca activation. 7 …”

Section: Discussionmentioning

confidence: 85%

“…9 For instance, BK Ca channels contribute to H 2 O 2 -induced dilation in porcine coronary arteries. 10,11 In contrast, 4-aminopyridine (4-AP)-sensitive K V channels mediate dilation to H 2 O 2 in canine coronary arteries, 12 rat coronary and mesenteric arteries, 12, 13 and porcine coronary resistance arteries. 14 Using coronary arterioles from CAD subjects, we found that H 2 O 2 opens smooth muscle BK Ca channels to elicit smooth muscle hyperpolarization and relaxation.…”

Section: Introductionmentioning

confidence: 99%

Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Nishijima

Cao

Chabowski

et al. 2017

Circulation Research

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Rationale Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating BKCa channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) as compared to those with CAD remain unknown. Objective We hypothesize that H2O2-elicited dilation involves different K+ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease. Methods and Results H2O2 induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a BKCa channel blocker, and by 4-AP, a KV channel blocker. Assays of mRNA transcripts, protein expression and subcellular localization revealed that KV1.5 is the major KV1 channel expressed in vascular smooth muscle cells (VSMCs) and is abundantly localized on the plasma membrane. The selective KV1.5 blocker DPO-1 and the KV1.3/1.5 blocker Psora-4 reduced H2O2-elicited dilation to a similar extent as 4-AP, but the selective KV1.3 blocker PAP-1 was without effect. In arterioles from CAD subjects, H2O2-induced dilation was significantly reduced and this dilation was inhibited by paxilline but not by 4-AP, DPO-1 or Psora-4. KV1.5 cell membrane localization and DPO-1-sensitive K+ currents were markedly reduced in isolated VSMCs from CAD arterioles, although mRNA or total cellular protein expression were largely unchanged. Conclusions In human arterioles, H2O2-induced dilation is impaired in CAD, which is associated with a transition from a combined BKCa- and KV (KV1.5)-mediated vasodilation toward a BKCa-predominant mechanism of dilation. Loss of KV1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.

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“…The potentiation was inhibited by tempol in the presence or absence of polyethylene glycol catalase (26), indicating a primary action of O 2 Ϫ rather than H 2 O 2 . Moreover, H 2 O 2 commonly acts as vasodilator in circulatory beds, such as cerebral, coronary, mesenteric, and skeletal muscle, and may function as an endotheliumdependent hyperpolarization factor and an activator of potassium channels (10,14,47,55,64,70); both dilator and hyperpolarizing actions are expected to blunt rather than potentiate pressure-induced myogenic constriction.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O₂⁻ dismutation on renal autoregulation in the time and frequency domains

Moss

Gentle

Arendshorst

2016

American Journal of Physiology-Renal Physiology

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Moss NG, Gentle TK, Arendshorst WJ. Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O 2 Ϫ dismutation on renal autoregulation in the time and frequency domains. Am J Physiol Renal Physiol 310: F832-F845, 2016. First published January 28, 2016 doi:10.1152/ajprenal.00461.2015.-Renal blood flow autoregulation was investigated in anesthetized C57Bl6 mice using time-and frequency-domain analyses. Autoregulation was reestablished by 15 s in two stages after a 25-mmHg step increase in renal perfusion pressure (RPP). The renal vascular resistance (RVR) response did not include a contribution from the macula densa tubuloglomerular feedback mechanism. Inhibition of nitric oxide (NO) synthase [N G -nitro-L-arginine methyl ester (L-NAME)] reduced the time for complete autoregulation to 2 s and induced 0.25-Hz oscillations in RVR. Quenching of superoxide (SOD mimetic tempol) during L-NAME normalized the speed and strength of stage 1 of the RVR increase and abolished oscillations. The slope of stage 2 was unaffected by L-NAME or tempol. These effects of L-NAME and tempol were evaluated in the frequency domain during random fluctuations in RPP. NO synthase inhibition amplified the resonance peak in admittance gain at 0.25 Hz and markedly increased the gain slope at the upper myogenic frequency range (0.06 -0.25 Hz, identified as stage 1), with reversal by tempol. The slope of admittance gain in the lower half of the myogenic frequency range (equated with stage 2) was not affected by L-NAME or tempol. Our data show that the myogenic mechanism alone can achieve complete renal blood flow autoregulation in the mouse kidney following a step increase in RPP. They suggest also that the principal inhibitory action of NO is quenching of superoxide, which otherwise potentiates dynamic components of the myogenic constriction in vivo. This primarily involves the first stage of a two-stage myogenic response. renal circulation; perfusion pressure; renal vascular resistance; admittance gain; afferent arteriole MOST VASCULAR BEDS REGULATE blood flow according to metabolic conditions to provide adequate nutrient delivery and effective waste removal. Control of renal blood flow (RBF) is unique among peripheral vascular beds, as the principal goal is not to satisfy metabolic demands, but rather to stabilize glomerular capillary pressure at a level that provides an adequate glomerular filtration rate. This is achieved by an efficient autoregulatory mechanism(s) that adjusts glomerular afferent arteriolar diameter in response to fluctuations in renal perfusion pressure (RPP). Of equal importance, this process protects glomerular capillaries from excessive pressures that can cause barotrauma, glomerular injury, and renal failure. Several intrinsic mechanisms regulate renal vascular resistance (RVR) in response to changes in RPP (3, 13). In common with most organs, changes in RPP invoke an intrinsic myogenic mechanism in the vascular smooth muscle cells (VSMC) of renal resistance vessels, which stabilizes dow...

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Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation

Cited by 47 publications

References 80 publications

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O₂⁻ dismutation on renal autoregulation in the time and frequency domains

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Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation

Cited by 47 publications

References 80 publications

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

Contribution of K V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O2− dismutation on renal autoregulation in the time and frequency domains

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Contribution of K _V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O₂⁻ dismutation on renal autoregulation in the time and frequency domains