scholarly journals Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

2020 ◽  
Vol 6 (16) ◽  
pp. eaba0694 ◽  
Author(s):  
Natascha Sommer ◽  
Nasim Alebrahimdehkordi ◽  
Oleg Pak ◽  
Fenja Knoepp ◽  
Ievgen Strielkov ◽  
...  
Keyword(s):  
Alternative Oxidase ◽  
Chronic Hypoxia ◽  
Electron Flux ◽  
Oxygen Sensing ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Initial Step ◽  
Complex Iii ◽  
Pulmonary Vasculature

Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

Hypoxic pulmonary vasoconstriction: role of ion channels

2005 ◽  
Vol 98 (1) ◽  
pp. 415-420 ◽  
Author(s):  
Joseph R. H. Mauban ◽  
Carmelle V. Remillard ◽  
Jason X.-J. Yuan
Keyword(s):  
Ion Channels ◽  
Structural Changes ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Vasculature ◽  
Cellular Mechanisms ◽  
Pulmonary Vasoconstriction ◽  
Intracellular Ca ◽  
Medial Hypertrophy

Acute hypoxia induces pulmonary vasoconstriction and chronic hypoxia causes structural changes of the pulmonary vasculature including arterial medial hypertrophy. Electro- and pharmacomechanical mechanisms are involved in regulating pulmonary vasomotor tone, whereas intracellular Ca2+ serves as an important signal in regulating contraction and proliferation of pulmonary artery smooth muscle cells. Herein, we provide a basic overview of the cellular mechanisms involved in the development of hypoxic pulmonary vasoconstriction. Our discussion focuses on the roles of ion channels permeable to K+ and Ca2+, membrane potential, and cytoplasmic Ca2+ in the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxia-mediated pulmonary vascular remodeling.

Oxygen-dependent signaling in pulmonary vascular smooth muscle

2002 ◽  
Vol 283 (4) ◽  
pp. L671-L677 ◽  
Author(s):  
Usha Raj ◽  
Larissa Shimoda
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Vasculature ◽  
Oxygen Oxygen ◽  
Smooth Muscle Function ◽  
Dependent Protein ◽  
Acute Increase

The pulmonary circulation constricts in response to acute hypoxia, which is reversible on reexposure to oxygen. On exposure to chronic hypoxia, in addition to vasoconstriction, the pulmonary vasculature undergoes remodeling, resulting in a sustained increase in pulmonary vascular resistance that is not immediately reversible. Hypoxic pulmonary vasoconstriction is physiological in the fetus, and there are many mechanisms by which the pulmonary vasculature relaxes at birth, principal among which is the acute increase in oxygen. Oxygen-induced signaling mechanisms, which result in pulmonary vascular relaxation at birth, and the mechanisms by which chronic hypoxia results in pulmonary vascular remodeling in the fetus and adult, are being investigated. Here, the roles of cGMP-dependent protein kinase in oxygen-mediated signaling in fetal pulmonary vascular smooth muscle and the effects of chronic hypoxia on ion channel activity and smooth muscle function such as contraction, growth, and gene expression were discussed.

scholarly journals Recent advances in oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

2017 ◽  
Vol 123 (6) ◽  
pp. 1647-1656 ◽  
Author(s):  
Ievgen Strielkov ◽  
Oleg Pak ◽  
Natasha Sommer ◽  
Norbert Weissmann
Keyword(s):  
Reactive Oxygen Species ◽  
Transient Receptor Potential ◽  
Oxygen Sensing ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Reactive Oxygen ◽  
Receptor Potential ◽  
Complex Iii ◽  
Oxygen Species ◽  
Pulmonary Vasoconstriction ◽  
Transient Receptor

Hypoxic pulmonary vasoconstriction (HPV) is a physiological reaction, which adapts lung perfusion to regional ventilation and optimizes gas exchange. Impaired HPV may cause systemic hypoxemia, while generalized HPV contributes to the development of pulmonary hypertension. The triggering mechanisms underlying HPV are still not fully elucidated. Several hypotheses are currently under debate, including a possible decrease as well as an increase in reactive oxygen species as a triggering event. Recent findings suggest an increase in the production of reactive oxygen species in pulmonary artery smooth muscle cells by complex III of the mitochondrial electron transport chain and occurrence of oxygen sensing at complex IV. Other essential components are voltage-dependent potassium and possibly L-type, transient receptor potential channel 6, and transient receptor potential vanilloid 4 channels. The release of arachidonic acid metabolites appears also to be involved in HPV regulation. Further investigation of the HPV mechanisms will facilitate the development of novel therapeutic strategies for the treatment of HPV-related disorders.

Divergent contractile and structural responses of the murine PKC-ε null pulmonary circulation to chronic hypoxia

2005 ◽  
Vol 289 (6) ◽  
pp. L1083-L1093 ◽  
Author(s):  
C. M. Littler ◽  
C. A. Wehling ◽  
M. J. Wick ◽  
K. A. Fagan ◽  
C. D. Cool ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Vascular Tone ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Structural Response ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Remodeling

Loss of PKC-ε limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-ε would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC-ε wild-type (PKC-ε+/+), heterozygous null, and homozygous null (PKC-ε−/−) mice were exposed to normoxia or Hx for 5 wk. PKC-ε−/− mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-ε+/+ mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-ε+/+ mice) in both the proximal and distal PKC-ε−/− pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-ε−/− mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-ε−/− than PKC-ε+/+ mice. In contrast, expression of nNOS in PKC-ε+/+ mice decreased in response to chronic Hx, while lung levels in PKC-ε−/− mice remained unchanged. In summary, loss of PKC-ε results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC-ε appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.

scholarly journals Inactivation of Tristetraprolin in Chronic Hypoxia Provokes the Expression of Cathepsin B

2014 ◽  
Vol 35 (3) ◽  
pp. 619-630 ◽  
Author(s):  
Dominik C. Fuhrmann ◽  
Michaela Tausendschön ◽  
Ilka Wittig ◽  
Mirco Steger ◽  
Martina G. Ding ◽  
...  
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Cathepsin B ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Rna Stability ◽  
Cellular Protein ◽  
Mrna Levels ◽  
Differential Gel Electrophoresis ◽  
Dependent Mechanism

Macrophages play important roles in many diseases and are frequently found in hypoxic areas. A chronic hypoxic microenvironment alters global cellular protein expression, but molecular details remain poorly understood. Although hypoxia-inducible factor (HIF) is an established transcription factor allowing adaption to acute hypoxia, responses to chronic hypoxia are more complex. Based on a two-dimensional differential gel electrophoresis (2D-DIGE) approach, we aimed to identify proteins that are exclusively expressed under chronic but not acute hypoxia (1% O2). One of the identified proteins was cathepsin B (CTSB), and a knockdown of either HIF-1α or -2α in primary human macrophages pointed to an HIF-2α dependency. Although chromatin immunoprecipitation (ChIP) experiments confirmed HIF-2 binding to a CTSB enhancer in acute hypoxia, an increase of CTSB mRNA was evident only under chronic hypoxia. Along those lines, CTSB mRNA stability increased at 48 h but not at 8 h of hypoxia. However, RNA stability at 8 h of hypoxia was enhanced by a knockdown of tristetraprolin (TTP). Inactivation of TTP under prolonged hypoxia was facilitated by c-Jun N-terminal kinase (JNK), and inhibition of this kinase lowered CTSB mRNA levels and stability. We postulate a TTP-dependent mechanism to explain delayed expression of CTSB under chronic hypoxia.

scholarly journals Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

2014 ◽  
Vol 306 (1) ◽  
pp. H41-H52 ◽  
Author(s):  
Carlos H. Nitta ◽  
David A. Osmond ◽  
Lindsay M. Herbert ◽  
Britta F. Beasley ◽  
Thomas C. Resta ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Arterial Remodeling ◽  
Ventricular Systolic Pressure ◽  
Intracellular Ca

Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH.

scholarly journals Intermittent hypoxia enhances the expression of HIF1A by increasing the quantity and catalytic activity of KDM4A-C and demethylating H3K9me3 at the HIF1A locus

2021 ◽  
Author(s):  
Chloe-Anne Martinez ◽  
Neha Bal ◽  
Peter A Cistulli ◽  
Kristina M Cook
Keyword(s):  
Intermittent Hypoxia ◽  
Target Genes ◽  
Chronic Hypoxia ◽  
Oxygen Sensing ◽  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Sensing Systems ◽  
Cellular Oxygen ◽  
Fine Tune

Cellular oxygen-sensing pathways are primarily regulated by hypoxia inducible factor-1 (HIF-1) in chronic hypoxia and are well studied. Intermittent hypoxia also occurs in many pathological conditions, yet little is known about its biological effects. In this study, we investigated how two proposed cellular oxygen sensing systems, HIF-1 and KDM4A-C, respond to cells exposed to intermittent hypoxia and compared to chronic hypoxia. We found that intermittent hypoxia increases HIF-1 activity through a pathway distinct from chronic hypoxia, involving the KDM4A, -B and -C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A-C resulting in a decrease in H3K9 methylation. This contrasts with chronic hypoxia, which decreases KDM4A-C activity, leading to hypermethylation of H3K9. Demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.

Abstract 2616: Role of the Soluble Epoxide Hydrolase in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Benjamin Keserü ◽  
Beate Fisslthaler ◽  
Ingrid Fleming
Keyword(s):  
Vascular Remodeling ◽  
Epoxide Hydrolase ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Soluble Epoxide Hydrolase ◽  
Pulmonary Vasculature ◽  
Resistance Arteries ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Vasoconstriction

The soluble epoxide hydrolase (sEH), which is expressed in pulmonary artery smooth muscle cells, metabolizes cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) to their less active diols. Preliminary findings indicate a role of the sEH on hypoxic pulmonary vasoconstriction (HPV) and a vasoconstrictor role of EETs in the pulmonary vasculature. Here we assessed the influence of hypoxia on the expression of the sEH, acute HPV and pulmonary vascular remodeling. In lungs from wild-type mice (WT), exposure to hypoxia (FiO 2 = 0.1) for 21 days decreased the expression of the sEH by 70% (RT-PCR), and increased the number of partially and fully muscularised resistance arteries (by 3-fold). In isolated lungs, pre-exposure to chronic hypoxia significantly increased baseline perfusion pressures (1.3-fold) and potentiated the acute HPV (1.5-fold). While an sEH inhibitor (1-adamantyl-3-cyclohexylurea; ACU) potentiated acute HPV in lungs from mice maintained in normoxic conditions, it had no effect on HPV in lungs from mice exposed to hypoxia. The EET antagonist, 14,15-EEZE, abolished the sEH inhibitor-dependent increase in acute HPV in normoxic lungs. Under normoxic conditions the muscularization of small pulmonary arteries was greater in lungs from sEH −/− mice than in lungs from WT mice and chronic hypoxia further increased the number of fully and partially muscularized arteries in these animals. sEH −/− mice also displayed an enhanced acute HPV (1.5-fold), compared to that observed in WT mice and chronic exposure to hypoxia did not further potentiate acute HPV. Taken together, these data indicate that the sEH is involved in hypoxia-induced pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction.

scholarly journals Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

2015 ◽  
Vol 47 (1) ◽  
pp. 288-303 ◽  
Author(s):  
Natascha Sommer ◽  
Ievgen Strielkov ◽  
Oleg Pak ◽  
Norbert Weissmann
Keyword(s):  
Signal Transduction ◽  
Calcium Channels ◽  
Transient Receptor Potential ◽  
Oxygen Sensing ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Transient Receptor Potential Channels ◽  
Pulmonary Vasculature ◽  
Experimental Conditions ◽  
Pulmonary Vasoconstriction ◽  
Alveolar Hypoxia

Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler–Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulatedin vivoby the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCsviadirect or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV.

scholarly journals Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

2013 ◽  
Vol 304 (2) ◽  
pp. R136-R146 ◽  
Author(s):  
Arlin B. Blood ◽  
Michael H. Terry ◽  
Travis A. Merritt ◽  
Demosthenes G. Papamatheakis ◽  
Quintin Blood ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
High Altitude ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Rho Kinase ◽  
In Vivo Studies ◽  
Significant Difference ◽  
Low Altitude

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca2+ entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

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