scholarly journals Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase

2005 ◽  
Vol 202 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Kanji Minamoto ◽  
Hiroaki Harada ◽  
Vibha N. Lama ◽  
Maksim A. Fedarau ◽  
David J. Pinsky
Keyword(s):  
Nitric Oxide ◽  
Heme Oxygenase ◽  
Soluble Guanylate Cyclase ◽  
Protoporphyrin Ix ◽  
Competitive Inhibitor ◽  
Binding Activity ◽  
Zinc Protoporphyrin ◽  
Reciprocal Regulation ◽  
Enhanced Expression ◽  
Lung Transplant Recipients

Obliterative bronchiolitis (OB) develops insidiously in nearly half of all lung transplant recipients. Although typically preceded by a CD8+ T cell–rich lymphocytic bronchitis, it remains unresponsive to conventional immunosuppression. Using an airflow permissive model to study the role of gases flowing over the transplanted airway, it is shown that prolonged inhalation of sublethal doses of carbon monoxide (CO), but not nitric oxide (NO), obliterate the appearance of the obstructive airway lesion. Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation. In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion. Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO. Hmox-1/CO decreased nuclear factor (NF)-κB binding activity to the iNOS promoter region and iNOS expression. Inhibition of soluble guanylate cyclase did not interfere with the ability of CO to suppress OB, implicating a cyclic guanosine 3′,5′-monophosphate–independent mechanism through which CO suppresses NF-κB, iNOS transcription, and OB. Prolonged CO inhalation represents a new immunosuppresive strategy to prevent OB.

scholarly journals A Protective Role for Heme Oxygenase Expression in Pancreatic Islets Exposed to Interleukin-1β**This work was supported by NIH Grant DK-25705 (to S.G.L.).

Endocrinology ◽  
1998 ◽  
Vol 139 (10) ◽  
pp. 4155-4163 ◽  
Author(s):  
Jing Ye ◽  
Suzanne G. Laychock
Keyword(s):  
Nitric Oxide ◽  
Protective Effect ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Heme Oxygenase ◽  
Protoporphyrin Ix ◽  
Interleukin 1Β ◽  
Zinc Protoporphyrin ◽  
Inhibitory Effects ◽  
Isolated Pancreatic Islets

Abstract Heme oxygenase (HO)-1 expression was investigated in rat isolated pancreatic islets. Freshly isolated islets showed no evidence of HO-1 expression. After a 20-h culture, there was a small increase in HO-1 in control islets, and interleukin-1β (IL-1β) induced HO-1 expression above control levels. NG-monomethyl-l-arginine inhibited the IL-1β-induced increase in HO-1. Sodium nitroprusside-generated nitric oxide also increased HO-1 expression. CoCl2 induced a concentration- and time-dependent increase in HO-1, but not heat shock protein 70, expression. Cobalt chloride (CoCl2) protected islets from the inhibitory effects of IL-1β on glucose-stimulated insulin release and glucose oxidation. Nickel chloride did not mimic the effects of CoCl2. An inhibitor of HO-1 activity, zinc-protoporphyrin IX (ZnPP), prevented the protective effect of CoCl2 on insulin release with IL-1β but did not affect HO-1 expression or the inhibitory response to IL-1β alone. ZnPP also inhibited the protective effect of hemin in IL-1β-treated islets. CoCl2 inhibited the marked increase in islet nitrite production in response to IL-1β. Cobalt-protoporphyrin IX (CoPP), which increased HO expression and activity, also protected islets from the inhibitory effects of IL-1β, even though IL-1β largely blocked the CoPP-induced increase in HO-1 expression. In βHC9 cells, CoCl2 increased HO-1 expression and HO activity, whereas CoPP directly activated HO. ZnPP inhibited basal and CoCl2-stimulated HO activity. Thus, increased HO-1 expression and/or HO activity in response to CoCl2, CoPP, and hemin, seems to mediate protective responses of pancreatic islets against IL-1β. HO-1 may be protective of β-cells because of the scavenging of free heme, the antioxidant effects of the end-product bilirubin, or the generation of carbon monoxide, which might have insulin secretion-promoting effects and inhibitory effects on nitric oxide synthase.

scholarly journals Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Simon C. M. Kwok
Keyword(s):  
Stress Response ◽  
Protein Kinase ◽  
Heme Oxygenase ◽  
Kinase Inhibitors ◽  
Protoporphyrin Ix ◽  
Competitive Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Transcriptional Level

Zinc protoporphyrin IX (ZnPP), a naturally occurring molecule formed in iron deficiency or lead poisoning, is a potent competitive inhibitor of heme oxygenase-1 (HO-1). It also regulates expression of HO-1 at the transcriptional level. However, the effect of ZnPP on HO-1 expression is controversial. It was shown to induce HO-1 expression in some cells, but suppress it in others. The objective of this study is to investigate the effect of ZnPP on HO-1 expression in prostate cancer PC-3 cells. Incubation of PC-3 cells with 10 μM ZnPP for 4 h showed only a slight induction of HO-1 mRNA and protein, but the induction was high after 16 h and was maintained through 48 h of incubation. Of all the known responsive elements in the HO-1 promoter, ZnPP activated mainly the stress response elements. Of the various protein kinase inhibitors and antioxidant tested, only Ro 31-8220 abrogated ZnPP-induced HO-1 expression, suggesting that activation of HO-1 gene by ZnPP may involve protein kinase C (PKC). The involvement of PKCα,β,δ,η,θ, andζisoforms was ruled out by the use of specific inhibitors. The isoform of PKC involved and participation of other transcription factors remain to be studied.

Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization

2003 ◽  
Vol 285 (1) ◽  
pp. H220-H228 ◽  
Author(s):  
Jay S. Naik ◽  
Benjimen R. Walker
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Heme Oxygenase ◽  
Vascular Reactivity ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Spin Traps ◽  
Enhanced Production ◽  
Vasodilatory Response ◽  
Presence And Absence

Chronic hypoxia is associated with both blunted agonist-induced and myogenic vascular reactivity and is possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the mechanism of endogenous CO-meditated vasodilation remains unclear. Isolated pressurized mesenteric arterioles from chronically hypoxic rats were administered the HO substrate heme-l-lysinate (HLL) in the presence or absence of iberiotoxin, 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), ryanodine, or free radical spin traps ( N- tert-butyl-α-phenylnitrone and 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt). The effects of HLL administration on vascular smooth muscle (VSM) membrane potential were assessed in superior mesenteric artery strips in the presence and absence of zinc protoporphyrin IX or iberiotoxin. The vasodilatory responses to exogenous CO were assessed in the presence and absence of ODQ or iberiotoxin. HLL administration produced a dose-dependent vasodilatory response that was nearly eliminated in the presence of iberiotoxin. Neither ODQ, spin traps, nor ryanodine altered the vasodilatory response to HLL, although ODQ abolished the vasodilatory response to S-nitroso- N-acetyl-penicillamine. HLL administration produced a zinc protoporphyrin IX- and iberiotoxin-sensitive VSM cell hyperpolarization. Iberiotoxin and ODQ inhibited the vasodilatory response to exogenous CO. Thus the vasodilatory response to endogenous CO involves cGMP-independent activation of VSM large-conductance Ca2+-activated K+ channels and does not likely involve the formation of Ca2+ sparks emanating from ryanodine-sensitive stores.

scholarly journals Role of heme oxygenase-2 in pial arteriolar response to acetylcholine in mice with and without transfusion of cell-free hemoglobin polymers

2008 ◽  
Vol 295 (2) ◽  
pp. R498-R504 ◽  
Author(s):  
Xinyue Qin ◽  
Herman Kwansa ◽  
Enrico Bucci ◽  
Sylvain Doré ◽  
Darren Boehning ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Heme Oxygenase ◽  
Oxygen Carrier ◽  
Protoporphyrin Ix ◽  
Cranial Window ◽  
Dilatory Response ◽  
A Cell ◽  
Oxide Synthase

Carbon monoxide derived from heme oxygenase (HO) may participate in cerebrovascular regulation under specific circumstances. Previous work has shown that HO contributes to feline pial arteriolar dilation to acetylcholine after transfusion of a cell-free polymeric hemoglobin oxygen carrier. The role of constitutive HO2 in the pial arteriolar dilatory response to acetylcholine was determined by using 1) HO2-null mice (HO2−/−), 2) the HO inhibitor tin protoporphyrin IX (SnPPIX), and 3) 4,5,6,7-tetrabromobenzotriazole (TBB), an inhibitor of casein kinase-2 (CK2)-dependent phosphorylation of HO2. In anesthetized mice, superfusion of a cranial window with SnPPIX decreased arteriolar dilation produced by 10 μM acetylcholine by 51%. After partial polymeric hemoglobin exchange transfusion, the acetylcholine response was normal but was reduced 72% by SnPPIX and 95% by TBB. In HO2−/− mice, the acetylcholine response was modestly reduced by 14% compared with control mice and was unaffected by SnPPIX. After hemoglobin transfusion in HO2−/− mice, acetylcholine responses were also unaffected by SnPPIX and TBB. In contrast, nitric oxide synthase inhibition completely blocked the acetylcholine responses in hemoglobin-transfused HO2−/− mice. We conclude 1) that HO2 activity partially contributes to acetylcholine-induced pial arteriolar dilation in mice, 2) that this contribution is augmented in the presence of a plasma-based hemoglobin polymer and appears to depend on a CK2 kinase mechanism, 3) that nitric oxide synthase activity rather than HO1 activity contributes to the acetylcholine reactivity in HO2−/− mice, and 4) that plasma-based polymeric hemoglobin does not scavenge all of the nitric oxide generated by cerebrovascular acetylcholine stimulation.

Inhibitory effect of CO on internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation

1993 ◽  
Vol 265 (4) ◽  
pp. G799-G804 ◽  
Author(s):  
S. Rattan ◽  
S. Chakder
Keyword(s):  
Smooth Muscle ◽  
Anal Sphincter ◽  
Heme Oxygenase ◽  
Nerve Stimulation ◽  
Internal Anal Sphincter ◽  
Direct Action ◽  
Second Messengers ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Before And After

We examined the effect and role of CO in opossum internal anal sphincter (IAS) relaxation in response to nonadrenergic noncholinergic (NANC) nerve stimulation. Effects of NANC nerve stimulation on the IAS tension and second messengers (cAMP and cGMP) were examined before and after the selective heme oxygenase (HO) inhibitor zinc protoporphyrin IX (Zn PP-IX). The HO activity of the IAS smooth muscle was determined before and after NANC nerve stimulation. CO caused a concentration-dependent and tetrodotoxin-resistant fall in the resting tension of the IAS. The direct action of CO was confirmed by its relaxant action on the isolated smooth muscle cells. Furthermore, CO caused an increase in the tissue cGMP levels comparable to that observed with nerve stimulation. Zn PP-IX caused suppression of IAS relaxation caused by NANC nerve stimulation and vasoactive intestinal polypeptide (VIP) but not by peptide histidine-isoleucine and suppression of the increase in cGMP in response to NANC nerve stimulation. Zn PP-IX had no significant effect on the IAS responses to CO, nitric oxide (NO), and the beta-adrenoceptor agonist isoproterenol. The IAS responses to CO were not modified by the NO synthase inhibitor NG-nitro-L-arginine. Significant HO activity was detected in the IAS, which increased further in response to NANC nerve stimulation and VIP. The direct relaxant actions of CO and the suppression of NANC-mediated relaxation of the IAS by the HO inhibitor suggest the involvement of CO in the neurally mediated IAS relaxation.

Hemin, a heme oxygenase-1 inducer, restores the attenuated cardioprotective effect of ischemic preconditioning in isolated diabetic rat heart

2016 ◽  
Vol 36 (8) ◽  
pp. 867-875 ◽  
Author(s):  
I Gupta ◽  
A Goyal ◽  
NK Singh ◽  
HN Yadav ◽  
PL Sharma
Keyword(s):  
Nitric Oxide ◽  
Heme Oxygenase ◽  
Ischemic Preconditioning ◽  
Rat Heart ◽  
Myocardial Infarct ◽  
Cardioprotective Effect ◽  
Diabetic Rat ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Myocardial Infarct Size

Background: Attenuated cardioprotective effect of ischemic preconditioning (IPC) by reduced nitric oxide (NO) is a hallmark during diabetes mellitus (DM). Recently, we reported that the formation of caveolin–endothelial nitric oxide synthase (eNOS) complex decreases the release of NO, which is responsible for attenuation of IPC-induced cardioprotection in DM rat heart. Heme oxygenase-1 (HO-1) facilitates release of NO by disrupting caveolin–eNOS complex. The activity of HO-1 is decreased during DM. This study was designed to investigate the role of hemin (HO-1 inducer) in attenuated cardioprotective effect of IPC in isolated diabetic rat heart. Methods: DM was induced in male Wistar rat by single dose of streptozotocin. Cardioprotective effect was assessed in terms of myocardial infarct size and release of lactate dehydrogenase and creatine kinase in coronary effluent. The release of NO was estimated indirectly by measuring the release of nitrite in coronary effluent. Perfusion of sodium nitrite, a precursor of NO, was used as a positive control. Result: IPC-induced cardioprotection and increased release of nitrite were significantly attenuated in a diabetic rat as compared to a normal rat. Pretreatment with hemin and daidzein, a caveolin inhibitor, alone or in combination significantly restored the attenuated cardioprotection and increased the release of nitrite in diabetic rat heart. Zinc protoporphyrin, a HO-1 inhibitor, significantly abolished the observed cardioprotection and decreased the release of nitrite in hemin pretreated DM rat heart. Conclusion: Thus, it is suggested that hemin restores the attenuated cardioprotective effect in diabetic rat heart by increasing the activity of HO-1 and subsequently release of NO.

Dopamine or transmitter release from rat carotid body may not be essential to hypoxic chemoreception

1994 ◽  
Vol 267 (6) ◽  
pp. R1632-R1639 ◽  
Author(s):  
M. K. Sun ◽  
D. J. Reis
Keyword(s):  
Nitric Oxide ◽  
Transmitter Release ◽  
Protoporphyrin Ix ◽  
Zinc Protoporphyrin ◽  
Tetraacetic Acid ◽  
Reactive Blue 2 ◽  
Afferent Nerves ◽  
Ganglionic Transmission ◽  
Oxide Synthase ◽  
Dose Dependent

In anesthetized, paralyzed, and ventilated rats, hypoxia or intracarotid cyanide excited the carotid chemoafferents, whereas intracarotid dopamine and tyramine inhibited the chemoafferent discharges. The inhibition was abolished by chlorpromazine without attenuating the hypoxic excitation. Comparably, the hypoxic excitation was not attenuated by the following: 1) inhibition of nitric oxide synthase with NG-nitro-L-arginine; 2) inhibition of heme oxygenase with zinc protoporphyrin IX; 3) antagonism of ATP receptors with reactive blue 2; 4) antagonism of cholinergic receptors with atropine or trimethaphan; 5) inactivation of adenosine with adenosine deaminase; and 6) blockade of glutamate receptors with kynurenate. Systemic administration of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N'N'-tetraacetic acid, in doses reversibly blocking sympathetic ganglionic transmission, was also without effect. Cyanide microinjection (0.05-0.5 nmol) into the petrosal but not nodose ganglion elicited a rapid dose-dependent elevation of arterial pressure. We conclude that excitation of the chemoreceptor afferents by hypoxia/cyanide cannot be attributed to release of these agents nor to others by Ca(2+)-dependent mechanisms. The results suggest that the afferent nerves themselves might function as oxygen detectors.

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