How Does the Heart Sense Changes in Oxygen Tension: A Role for Ion Channels?

Hool, Livia C.

doi:10.1089/ars.2014.5880

Cited by 8 publications

(6 citation statements)

References 127 publications

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“…It has been proposed that the short NT isoform contains an “oxygen sensing region” encoded by exon 45 15 . We have previously demonstrated that hypoxia does not directly alter the function of the long NT isoform or the short NT isoform reconstituted in proteoliposomes 16 . If this is true, the channel must be responding as a “redox sensor”.…”

Section: Discussionmentioning

confidence: 95%

“…It has been proposed that the Ca v 1.2 protein contains an “oxygen sensing region” encoded by exon 45 15 . However, a direct effect of hypoxia on Ca v 1.2 function has not been demonstrated 16 . In addition, thiol reducing agents have been demonstrated to mimic the effects of hypoxia on Ca 2+ currents while thiol oxidising agents increase Ca 2+ currents or attenuate the effects of hypoxia 13 14 17 18 19 20 21 22 23 24 .…”

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confidence: 99%

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Evidence for redox sensing by a human cardiac calcium channel

Muralidharan

Szappanos

Ingley

et al. 2016

Sci Rep

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Ion channels are critical to life and respond rapidly to stimuli to evoke physiological responses. Calcium influx into heart muscle occurs through the ion conducting α1C subunit (Cav1.2) of the L-type Ca2+ channel. Glutathionylation of Cav1.2 results in increased calcium influx and is evident in ischemic human heart. However controversy exists as to whether direct modification of Cav1.2 is responsible for altered function. We directly assessed the function of purified human Cav1.2 in proteoliposomes. Truncation of the C terminus and mutation of cysteines in the N terminal region and cytoplasmic loop III-IV linker did not alter the effects of thiol modifying agents on open probability of the channel. However mutation of cysteines in cytoplasmic loop I-II linker altered open probability and protein folding assessed by thermal shift assay. We find that C543 confers sensitivity of Cav1.2 to oxidative stress and is sufficient to modify channel function and posttranslational folding. Our data provide direct evidence for the calcium channel as a redox sensor that facilitates rapid physiological responses.

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Section: Discussionmentioning

confidence: 95%

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confidence: 99%

Evidence for redox sensing by a human cardiac calcium channel

Muralidharan

Szappanos

Ingley

et al. 2016

Sci Rep

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“…The mechanism by which lowering PO 2 differentially regulates L-type Ca 2+ channels expressed in PASMCs is not known. It has been reported that the pore-forming subunit of L-type channels (α1C or Cav 1.2) expressed in the heart has specific cysteine residues whose oxidation could increase the probability of channel opening (Hool, 2015;Muralidharan et al, 2016). This fact would explain the increase in voltage-dependent Ca 2+ current in pulmonary resistance myocytes.…”

Section: Calcium Channelsmentioning

confidence: 99%

“…Studies performed using mutated α1C subunits with replacement of specific cysteine residues have shown that the L-type Ca 2+ channels are indeed redox sensors although the effects of ROS on these channels are a matter of controversy (Hool, 2015;Muralidharan et al, 2016). Direct modification by oxidants of thiol groups in purified L-type Ca 2+ channels reconstituted in proteoliposomes increases channel open probability, while reducing agents have the opposite effect (Hool, 2015).…”

Section: Voltage-dependent Ca 2+ Channelsmentioning

confidence: 99%

Acute oxygen sensing by vascular smooth muscle cells

Moreno‐Domínguez

Colinas²,

Smani³

et al. 2023

Front. Physiol.

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An adequate supply of oxygen (O2) is essential for most life forms on earth, making the delivery of appropriate levels of O2 to tissues a fundamental physiological challenge. When O2 levels in the alveoli and/or blood are low, compensatory adaptive reflexes are produced that increase the uptake of O2 and its distribution to tissues within a few seconds. This paper analyzes the most important acute vasomotor responses to lack of O2 (hypoxia): hypoxic pulmonary vasoconstriction (HPV) and hypoxic vasodilation (HVD). HPV affects distal pulmonary (resistance) arteries, with its homeostatic role being to divert blood to well ventilated alveoli to thereby optimize the ventilation/perfusion ratio. HVD is produced in most systemic arteries, in particular in the skeletal muscle, coronary, and cerebral circulations, to increase blood supply to poorly oxygenated tissues. Although vasomotor responses to hypoxia are modulated by endothelial factors and autonomic innervation, it is well established that arterial smooth muscle cells contain an acute O2 sensing system capable of detecting changes in O2 tension and to signal membrane ion channels, which in turn regulate cytosolic Ca2+ levels and myocyte contraction. Here, we summarize current knowledge on the nature of O2 sensing and signaling systems underlying acute vasomotor responses to hypoxia. We also discuss similarities and differences existing in O2 sensors and effectors in the various arterial territories.

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“…These authors reported PO 2 -related decreases in myocardial work and power even when oxygen levels were well above physiological and suggested that this result was due to a mechanism other than reduced energy supply. Several potential oxygen sensing mechanisms have been identified in cardiac tissue [including H 2 S, NO, ROS, and ion (Ca 2ϩ ) channels (13,23,47,55)], and it is possible that these mechanisms were more sensitive to changes in PO 2 in hypoxic-acclimated trout.…”

Section: Impact Of Acute and Chronic Hypoxia On Myocardial Work And Power Outputmentioning

confidence: 99%

Hypoxic acclimation negatively impacts the contractility of steelhead trout (Oncorhynchus mykiss) spongy myocardium

Carnevale

Roberts

Syme

et al. 2020

American Journal of Physiology-Regulatory, Integrative and Comp

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Cardiac stroke volume (SV) is compromised in Atlantic cod and rainbow trout following acclimation to hypoxia (i.e., 40% air saturation; ~8 kPa O2) at 10–12°C, and this is not due to changes in heart morphometrics or maximum achievable in vitro end-diastolic volume. To examine if this diminished SV may be related to compromised myocardial contractility, we used the work-loop method to measure work and power in spongy myocardial strips from normoxic- and hypoxic-acclimated steelhead trout when exposed to decreasing Po2 levels (21 to 1.5 kPa) at several frequencies (30–90 contractions/min) at 14°C (their acclimation temperature). Work required to lengthen the muscle, as during filling of the heart, was strongly frequency dependent (i.e., increased with contraction rate) but was not affected by hypoxic acclimation or test Po2. In contrast, although shortening work was less frequency dependent, this parameter and network (and power) 1) were consistently lower (by ~30–50 and ~15%, respectively) in strips from hypoxic-acclimated fish and 2) fell by ~40–50% in both groups from 20 to 1.5 kPa Po2, despite the already-reduced myocardial performance in the hypoxic-acclimated group. In addition, strips from hypoxic-acclimated trout showed a poorer recovery of net power (by ~15%) when returned to normoxia. These results strongly suggest that hypoxic acclimation reduces myocardial contractility, and in turn, may limit SV (possibly by increasing end-systolic volume), but that this diminished performance does not improve the capacity to maintain myocardial performance under oxygen limiting conditions.

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How Does the Heart Sense Changes in Oxygen Tension: A Role for Ion Channels?

Abstract: A further understanding of these cellular processes should result in interventions that assist in preventing the deleterious effects of acute changes in oxygen tension such as alterations in contractile function and cardiac arrhythmia.

Cited by 8 publications

References 127 publications

Evidence for redox sensing by a human cardiac calcium channel

Evidence for redox sensing by a human cardiac calcium channel

Acute oxygen sensing by vascular smooth muscle cells

Hypoxic acclimation negatively impacts the contractility of steelhead trout (Oncorhynchus mykiss) spongy myocardium

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