Abstract 276: Heme Oxygenase-1 Induction Modulates Hypoxic Pulmonary Vasoconstriction

Endothelium removed Bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving lowering of superoxide-derived hydrogen peroxide and removing its basal relaxing effect. Induction of heme oxygenase-1 (HO-1) in BPA by 24 hr organ culture with 0.1mM cobalt chloride was accompanied by a decrease in 5μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to 20mM KCl in BPA was not affected by HO-1, but hypoxic pulmonary vasoconstriction (HPV) was significantly reduced. Organ culture with a HO-1 inhibitor (10μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Pretreatment of BPA with a copper chelator 10mM diethyldithiocarbamate (DETCA) to inactivate Cu,Zn-SOD, prevented the conversion of superoxide to peroxide, and attenuated HPV. DETCA treatment increased superoxide and decreased peroxide to similar levels in control and HO-1 induced BPA. Peroxide scavenging with 0.1mM ebselen increased force development to 20mM KCl and partially reversed the decrease in HPV seen on induction of HO-1. Thus HO-1 induction in BPA causes an increase in superoxide scavenging by Cu,Zn-SOD resulting in increased levels of peroxide, leading to an attenuation of HPV. The generation of superoxide in BPA is not affected by HO-1 induction as DETCA treated control and HO-1 BPA show similar levels of superoxide. Thus, HO-1 induction appears to attenuate HPV in BPA by increasing the conversion of superoxide to peroxide, leading to peroxide levels which may not be adequately lowered by hypoxia.

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Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00315.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. H1453-H1461 ◽

Cited By ~ 20

Author(s):

Mansoor Ahmad ◽

Xiangmin Zhao ◽

Melissa R. Kelly ◽

Sharath Kandhi ◽

Oscar Perez ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Heme Oxygenase ◽

Cobalt Chloride ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Heme Oxygenase 1 ◽

Force Development ◽

Pulmonary Vasoconstriction ◽

Copper Chelator ◽

Expression And Activity

Endothelium-denuded bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving removing a superoxide-derived hydrogen peroxide-mediated relaxation. BPA organ cultured for 24 h with 0.1 mM cobalt chloride (CoCl2) to increase the expression and activity of heme oxygenase-1 (HO-1) is accompanied by a decrease in 5 μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to KCl in BPA was not affected by increases in HO-1, but the hypoxic pulmonary vasoconstriction (HPV) response was decreased. Organ culture with a HO-1 inhibitor (10 μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Treatment of HO-1-induced BPA with extracellular catalase resulted in reversal of the attenuation of HPV without affecting the force development to KCl. Increasing intracellular peroxide scavenging with 0.1 mM ebselen increased force development to KCl and partially reversed the decrease in HPV seen on induction of HO-1. HO-1 induction increases extracellular (ec) superoxide dismutase (SOD) expression without changing Cu,Zn-SOD and Mn-SOD levels. HO-1-induced BPA rings treated with the copper chelator 10 mM diethyldithiocarbamate to inactivate ecSOD and Cu,Zn-SOD showed increased superoxide and decreased peroxide to levels equal to non-HO-1-induced rings, whereas the addition of SOD to freshly isolated BPA rings attenuated HPV similar to HO-1 induction with CoCl2. Therefore, HO-1 induction in BPA increases ecSOD expression associated with enhanced generation of peroxide in amounts that may not be adequately removed during hypoxia, leading to an attenuation of HPV.

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Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00846.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. H1244-H1250 ◽

Cited By ~ 12

Author(s):

Christopher J. Mingone ◽

Mansoor Ahmad ◽

Sachin A. Gupte ◽

Joseph L. Chow ◽

Michael S. Wolin

Keyword(s):

Nitric Oxide ◽

Pulmonary Artery ◽

Organ Culture ◽

Heme Oxygenase ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Pulmonary Arteries ◽

Heme Oxygenase 1 ◽

No Donor ◽

Spermine Nonoate

This study examines in endothelium-denuded bovine pulmonary arteries the effects of increasing heme oxygenase-1 (HO-1) activity on relaxation and soluble guanylate cyclase (sGC) activation by nitric oxide (NO). A 24-h organ culture with 0.1 mM cobalt chloride (CoCl2) or 30 μM Co-protoporphyrin IX was developed as a method of increasing HO-1 expression. These treatments increased HO-1 expression and HO activity by approximately two- to fourfold and lowered heme levels by 40–45%. Induction of HO-1 was associated with an attenuation of pulmonary arterial relaxation to the NO-donor spermine-NONOate. The presence of a HO-1 inhibitor 30 μM chromium mesoporphyrin during the 24-h organ culture (but not acute treatment with this agent) reversed the attenuation of relaxation to NO seen in arteries co-cultured with agents that increased HO-1. Relaxation to isoproterenol, which is thought to be mediated through cAMP, was not altered in arteries with increased HO-1. Inducers of HO-1 did not appear to alter basal sGC activity in arterial homogenates or expression of the β1-subunit of sGC. However, the increase in activity seen in the presence of 1 μM spermine-NONOate was attenuated in homogenates obtained from arteries with increased HO-1. Since arteries with increased HO-1 had decreased levels of superoxide detected by the chemiluminescence of 5 μM lucigenin, superoxide did not appear to be mediating the attenuation of relaxation to NO. These data suggest that increasing HO-1 activity depletes heme, and this is associated with an attenuation of pulmonary artery relaxation and sGC activation responses to NO.

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Heme Oxygenase‐1 Induction Modulates Hypoxic Pulmonary Vasoconstriction through Upregulation of ecSOD

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.1002.9 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Mansoor Ahmad ◽

Sharath Kandhi ◽

Xiangmin Zhao ◽

Melissa R Kelly ◽

Sri Krishna Chaitanya Arudra ◽

...

Keyword(s):

Heme Oxygenase ◽

Hypoxic Pulmonary Vasoconstriction ◽

Heme Oxygenase 1 ◽

Pulmonary Vasoconstriction

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Involvement of Heme Oxygenase-1 in particulate matter-induced impairment of NO-dependent relaxation in rat intralobar pulmonary arteries

Toxicology in Vitro ◽

10.1016/j.tiv.2016.01.005 ◽

2016 ◽

Vol 32 ◽

pp. 205-211 ◽

Cited By ~ 4

Author(s):

Marjorie Barrier ◽

Marc-Antoine Bégorre ◽

Isabelle Baudrimont ◽

Mathilde Dubois ◽

Véronique Freund-Michel ◽

...

Keyword(s):

Particulate Matter ◽

Heme Oxygenase ◽

Pulmonary Arteries ◽

Heme Oxygenase 1

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Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00044.2005 ◽

2005 ◽

Vol 289 (1) ◽

pp. L5-L13 ◽

Cited By ~ 87

Author(s):

Letitia Weigand ◽

Joshua Foxson ◽

Jian Wang ◽

Larissa A. Shimoda ◽

J. T. Sylvester

Keyword(s):

Hypoxic Pulmonary Vasoconstriction ◽

Acute Hypoxia ◽

Pulmonary Arteries ◽

Cation Channels ◽

Pulmonary Vasoconstriction ◽

Nonselective Cation Channels ◽

Pressor Responses ◽

Intracellular Ca ◽

Pulmonary Arterial

Previous studies indicated that acute hypoxia increased intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, and capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca2+-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl2, and LaCl3) on pulmonary arterial pressor responses to 2% O2 and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca2+]i responses to hypoxia in PASMC, SKF-96365 and NiCl2 prevented and reversed HPV but did not alter pressor responses to KCl. At 10 μM, LaCl3 had similar effects, but higher concentrations (30 and 100 μM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca2+-free perfusate and the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca2+ through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca2+ on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

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Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat

Journal of Applied Physiology ◽

10.1152/jappl.1985.59.5.1389 ◽

1985 ◽

Vol 59 (5) ◽

pp. 1389-1393 ◽

Cited By ~ 73

Author(s):

D. R. Harder ◽

J. A. Madden ◽

C. Dawson

Keyword(s):

Action Potentials ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Input Resistance ◽

Potential Generation ◽

Applied Current ◽

Pulmonary Vasoconstriction ◽

Ionic Conductances ◽

The Relationship ◽

K Permeability

Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30–50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.

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Development of the pulmonary vasculature in newborn lambs: structure-function relationships

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.3.1255 ◽

1991 ◽

Vol 70 (3) ◽

pp. 1255-1264 ◽

Cited By ~ 18

Author(s):

R. P. Michel ◽

J. B. Gordon ◽

K. Chu

Keyword(s):

Light Microscopy ◽

Hypoxic Pulmonary Vasoconstriction ◽

Venous Pressure ◽

Pulmonary Arteries ◽

Muscle Thickness ◽

Pulmonary Vasculature ◽

Pressure Gradients ◽

Middle Segment ◽

Pulmonary Vasoconstriction ◽

Quantitative Light Microscopy

Our objectives were 1) to describe the quantitative light microscopy and ultrastructure of newborn lamb lungs and 2) to correlate hemodynamic changes during normoxia and hypoxia with the morphology. By light microscopy, we measured the percent muscle thickness (%MT) and peripheral muscularization of pulmonary arteries and veins from 25 lambs aged less than 24 h, 2-4 days, 2 wk, and 1 mo. At the same ages, lungs were isolated and perfused in situ and, after cyclooxygenase blockade with indomethacin, total, arterial (delta Pa), middle (delta Pm), and venous pressure gradients at inspired O2 fractions of 0.28 (mild hyperoxia) and 0.04 (hypoxia) were determined with inflow-outflow occlusion. During mild hyperoxia, delta Pa and delta Pm fell significantly between 2-4 days and 2 wk, whereas during hypoxia, only delta Pm fell. The %MT of all arteries (less than 50 to greater than 1,000 microns diam) decreased, and peripheral muscularization of less than 100-microns-diam arteries fell between less than 4 days and greater than 2 wk. Our data suggest that 1) the %MT of arteries determines normoxic pulmonary vascular resistance, because only arterial and middle segment resistance fell, 2) peripheral muscularization is a major determinant of hypoxic pulmonary vasoconstriction, because we observed a fall with age in peripheral muscularization of less than 100-micron-diam arteries and in delta Pm with hypoxia, and 3) the arterial limit of the middle segment defined by inflow-outflow occlusion lies in 100- to 1,000-microns-diam arteries.

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Responses of isolated guinea pig pulmonary venules to hypoxia and anoxia

Journal of Applied Physiology ◽

10.1152/jappl.1989.67.5.2147 ◽

1989 ◽

Vol 67 (5) ◽

pp. 2147-2153 ◽

Cited By ~ 8

Author(s):

W. R. Tracey ◽

J. T. Hamilton ◽

I. D. Craig ◽

N. A. Paterson

Keyword(s):

Guinea Pig ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Major Site ◽

Sustained Contraction ◽

Pulmonary Vasoconstriction ◽

Ph Dependent

Because small pulmonary arteries are believed to be the major site of hypoxic pulmonary vasoconstriction (HPV), pulmonary venular responses to hypoxia have received little attention. Therefore the responses of isolated guinea pig pulmonary venules to hypoxia (bath PO2, 25 Torr) and anoxia (bath PO2, 0 Torr) were characterized. Pulmonary venules [effective lumen radius (ELR), 116 +/- 2 microns] with an adherent layer of parenchyma responded to hypoxia and anoxia with a graded sustained contraction (hypoxia, 0.03 +/- 0.01; anoxia, 0.26 +/- 0.03 mN/mm), whereas paired femoral venules (ELR, 184 +/- 7 microns) contracted to anoxia only (0.05 +/- 0.02 mN/mm). Repeated challenges with hypoxia and anoxia continued to elicit sustained pulmonary venular contractions; femoral venule contractions to anoxia were not repeatable. Hypoxia- and anoxia-induced pulmonary venular contractions were calcium and pH dependent. Dissection of the parenchyma from pulmonary venules did not alter contractions to decreased PO2. Anoxic contractions of pulmonary venules were variably reduced by replacement of the bath fluid; however, the release of a contractile mediator(s) from pulmonary venules during hypoxia or anoxia was not demonstrated. Pulmonary venular responses to hypoxia and anoxia are similar to those induced by hypoxia in vivo, and results obtained from this model may be useful in predicting mechanisms of HPV.

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