Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

Patel, Dhara; Alhawaj, Raed; Wolin, Michael S.

doi:10.1152/ajpregu.00257.2013

Cited by 16 publications

(14 citation statements)

References 28 publications

(44 reference statements)

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“…For example, mitochondrial superoxide scavengers, which function in a manner similar to Mito-TEMPOL, have the potential for being effective in attenuating the disruption of heme biosynthesis, and Mito-TEMPO has been reported to attenuate vascular dysfunction in the ANG II infusion model (6,17). ALA has already been demonstrated to prevent hypoxia-induced pulmonary hypertension in mice (1,24). Although ALA was not protective in a mouse renal ischemia-reperfusion injury model, when used in combination with ferrous iron, it was protective as a result of generating heme in amounts that appeared to both induce and support the beneficial actions of heme oxygenase (8).…”

Section: Discussionmentioning

confidence: 99%

Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II

Patel

Alhawaj

Kelly

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Oxidation of the soluble guanylate cyclase (sGC) heme promotes loss of regulation by nitric oxide (NO) and depletion of sGC. We hypothesized that angiotensin II (ANG II) stimulation of mitochondrial superoxide by its type 1 receptor could function as a potential inhibitor of heme biosynthesis by ferrochelatase, and this could decrease vascular responsiveness to NO by depleting sGC. These processes were investigated in a 24-h organoid culture model of bovine coronary arteries (BCA) with 0.1 μM ANG II. Treatment of BCA with ANG II increased mitochondrial superoxide, depleted mitochondrial superoxide dismutase (SOD2), ferrochelatase, and cytochrome oxidase subunit 4, and sGC, associated with impairment of relaxation to NO. These processes were attenuated by organoid culture with 8-bromo-cGMP and/or δ-aminolevulinic acid (a stimulator of sGC by protoporphyrin IX generation and heme biosynthesis). Organoid culture with Mito-TEMPOL, a scavenger of mitochondrial matrix superoxide, also attenuated ANG II-elicited ferrochelatase depletion and loss of relaxation to NO, whereas organoid culture with Tempol, an extramitochondrial scavenger of superoxide, attenuated the loss of relaxation to NO by ANG II, but not ferrochelatase depletion, suggesting cytosolic superoxide could be an initiating factor in the loss of sGC regulation by NO. The depletion of cytochrome oxidase subunit 4 and sGC (but not catalase) suggests that sGC expression may be very sensitive to depletion of heme caused by ANG II disrupting ferrochelatase activity by increasing mitochondrial superoxide. In addition, cGMP-dependent activation of protein kinase G appears to attenuate these ANG II-stimulated processes through both preventing SOD2 depletion and increases in mitochondrial and extramitochondrial superoxide.

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Section: Discussionmentioning

confidence: 99%

Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II

Patel

Alhawaj

Kelly

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Increased mitochondrial superoxide elevation is believed to be one of the triggers for vascular remodeling that takes place in chronic hypoxia-induced pulmonary hypertension (8). Whereas ALA provides PPIX used for the production of heme needed for NO stimulation of sGC, it will also increase PPIX to levels that can also elevate cGMP and activate PKG (29,32), and this mechanism may be favored when heme biosynthesis by FECH is disrupted. Both of these processes stimulating PKG could function during prolonged treatment with ALA to attenuate the persistent vasoconstriction and vascular remodeling elicited by chronic exposure to hypoxia and perhaps other factors promoting pulmonary hypertension through processes hypothesized in the model shown in Fig.…”

Section: Et)mentioning

confidence: 99%

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Alhawaj

Patel

Kelly

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alhawaj R, Patel D, Kelly MR, Sun D, Wolin MS. Heme biosynthesis modulation via ␦-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308: L719 -L728, 2015. First published February 6, 2015 doi:10.1152/ajplung.00155.2014.-This study examines how heme biosynthesis modulation with ␦-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. endothelin; ferrochelatase; guanylate cyclase; micro-RNA 204; superoxide CHRONIC HYPOXIA IS AN IMPORTANT factor in the development of pulmonary hypertension in diseases such as chronic obstructive pulmonary disease (COPD), sleep apnea, and mountain sickness (10,20). It is thought to promote pulmonary hypertension development through persistent pulmonary vasoconstriction and vascular remodeling (31). There is substantial evidence for increases in the generation of reactive oxygen species from sources including Nox oxidases and mitochondria having important roles in the development and/or progression of pulmonary hypertension caused by chronic hypoxia and other stimuli of this disease process (7,15,18,27,30). Pulmonary arterial generation of nitric oxide (NO) is normally thought to oppose this process of vasoconstriction ...

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“…The incidence of supraventricular arrhythmias, including sinus bradycardia, atrioventricular block, atrial flutter and atrial fibrillation is high in patients with pHTN 18,19 . Wild type mice were subjected to continuously normoxic (21% O 2 ) or hypoxic (10% O 2 ) conditions for four weeks in an in vivo cabinet, as previously described 20, 21 . As expected, mean right atrial pressure is significantly increased in chronic hypoxia mice (Supplemental Table II) and expression of the direct Notch target Nrarp is significantly elevated in the pHTN model when compared with controls (Figure 1A, Supplemental Table I).…”

Section: Resultsmentioning

confidence: 99%

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice

Qiao

Lipovsky

Hicks

et al. 2017

Circulation Research

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Rationale Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes. Objective To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility. Methods and Results To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (iNICD). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including Nkx2-5, Tbx3 and Tbx5 are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including Scn5a (Nav1.5) and Gja5 (connexin 40), are persistently down-regulated long after a transient Notch pulse. Consistent with the reduction in Scn5a transcript, Notch induces global changes in the atrial action potential, including a reduced dVm/dtmax. In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology, and predisposes to an arrhythmogenic substrate. Conclusions Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes resulting in sinus bradycardia, sinus pauses and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome.

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Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

Cited by 16 publications

References 28 publications

Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II

Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice

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