scholarly journals Protein Therapy Using Heme-Oxygenase-1 Fused to a Polyarginine Transduction Domain Attenuates Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage

2011 ◽  
Vol 31 (11) ◽  
pp. 2231-2242 ◽  
Author(s):  
Tomoyuki Ogawa ◽  
Daniel Hänggi ◽  
Yumei Wu ◽  
Hiroyuki Michiue ◽  
Kazuhito Tomizawa ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Therapeutic Effect ◽  
Cerebral Vasospasm ◽  
Heme Oxygenase ◽  
Fluorescent Protein ◽  
Male Rats ◽  
Heme Oxygenase 1 ◽  
Protein Transduction ◽  
Arginine Residues ◽  
Basilar Arteries

A sequence of 11 consecutive arginine residues (11R) is one of the best protein transduction domains for introducing proteins into cell membranes. Heme-oxygenase-1 (HO-1) is involved in heme catabolism and reduces the contractile effect of hemoglobin after subarachnoid hemorrhage (SAH). Therefore, we constructed 11R-fused HO-1 protein to achieve successful transduction of the protein into the cerebral arteries and examined the therapeutic effect of the 11R-HO-1 protein for cerebral vasospasm (CV) after SAH. We injected the 11R-HO-1 protein into the cisterna magna of male rats and, several hours after the injection, performed immunofluorescence staining and western blotting analysis of the rat basilar arteries (BAs) to determine transduction efficacy. We also assessed intraarterial HO-1 activity as cGMP (cyclic guanosine 3′, 5′-cyclic monophosphate) accumulation in SAH and determined whether protein transduction of 11R-HO-1 quantified the therapeutic effect in a rat double-hemorrhage model of SAH. The BAs expressed significantly more HO-1 in the group injected with 11R-HO-1 (3.56±0.54 (11R-HO-1) versus control (saline)), and transduction of 11R-HO-1 resulted in higher activity (>3.25-fold) in rat BAs with SAH. Moreover, the results of the rat double-hemorrhage model showed that the 11R-HO-1 protein significantly attenuated CV after SAH (317.59±23.48 μm (11R-HO-1) versus 270.08±14.66 μm (11R-fused enhanced green fluorescent protein), 252.05±13.95 μm (saline), P<0.01).

Upregulation of estrogen receptor α and mediation of 17β-estradiol vasoprotective effects via estrogen receptor α in basilar arteries in rats after experimental subarachnoid hemorrhage

2008 ◽  
Vol 109 (1) ◽  
pp. 92-99 ◽  
Author(s):  
Huei-Chuan Shih ◽  
Chih-Lung Lin ◽  
Shu-Chuan Wu ◽  
Aij-Lie Kwan ◽  
Yi-Ren Hong ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Estrogen Receptor Α ◽  
Male Rats ◽  
Enos Expression ◽  
Basilar Arteries ◽  
17Β Estradiol ◽  
Oxide Synthase

Object The authors previously demonstrated that 17β-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)–induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERα and -β and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERα and -β in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated. Methods A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERα and -β expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERα- (methyl-piperidinopyrazole [MPP]) or ERβ-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERα, ERβ, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription–polymerase chain reaction. Results The ERα but not the ERβ was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression. Conclusions Estrogen receptor α is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERα-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERα agonist may be the drug of choice for the treatment of patients with SAH.

Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm

2009 ◽  
Vol 620 (1-3) ◽  
pp. 16-20 ◽  
Author(s):  
Yasuhito Shimada ◽  
Hiroshi Tsunoda ◽  
Liqing Zang ◽  
Minoru Hirano ◽  
Takehiko Oka ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Delayed Cerebral Vasospasm ◽  
Synergistic Induction

Dexrazoxane does not protect against doxorubicin-induced damage in young rats

2003 ◽  
Vol 285 (2) ◽  
pp. H499-H506 ◽  
Author(s):  
Stéphanie Héon ◽  
Martin Bernier ◽  
Nicolas Servant ◽  
Stevan Dostanic ◽  
Chunlei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Weight Gain ◽  
Heme Oxygenase ◽  
Caspase 3 ◽  
Exercise Program ◽  
Female Rats ◽  
Male Rats ◽  
Heme Oxygenase 1 ◽  
Cardiac Damage

Doxorubicin (DOX), an anticancer drug, causes a dose-dependent cardiotoxicity. Some evidence suggests that female children have an increased risk for DOX-mediated cardiac damage. To determine whether the iron chelator dexrazoxane (DXR) could reduce DOX-induced cardiotoxicity in the young, we injected day 10 neonate female and male rat pups with a single dose of saline or DOX, DXR, or DXR + DOX (20:1). We followed body weight gain with growth, measured cardiac hypertrophy after a 2-wk swim exercise program, markers of apoptosis (Bcl-2, BAX, BNIP1, caspase 3 activation), oxidative stress (heme oxygenase 1, protein carbonyl levels), the chaperone protein clusterin, and the transcriptional activator early growth response gene-1 (Egr-1) in hearts of nonexercised and exercised rats on neonate day 38. All DOX-alone and DXR + DOX-treated rats showed decreased weight gain, with female rats affected earlier than male rats. DXR-alone, DOX-alone, and DXR + DOX-treated rats had an increased heart weight-to-body weight (heart wt/body wt) ratio after the exercise program with female rats showing the largest increase in heart wt/body wt. Drug-treated females also showed increased cardiac apoptosis, as measured by the increased expression of the proapoptotic proteins BAX and BNIP1 and the appearance of caspase 3 activation products, and oxidative stress, as measured by increased heme oxygenase 1 expression, and reduced Egr-1 and clusterin expression when compared with the similarly treated male rats. We conclude that DXR preinjection did not reduce DOX-induced noncardiac and cardiac damage and that young female rats were more susceptible to DXR and DOX toxicities than age-matched male rats.

scholarly journals Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus

Viruses ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 2 ◽  
Author(s):  
Chaker El Kalamouni ◽  
Etienne Frumence ◽  
Sandra Bos ◽  
Jonathan Turpin ◽  
Brice Nativel ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Heme Oxygenase ◽  
Zika Virus ◽  
Fluorescent Protein ◽  
Human Cells ◽  
Heme Oxygenase 1 ◽  
Viral Inhibition ◽  
Reporter Protein ◽  
Wide Range ◽  
Rna Replicon

Heme oxygenase-1 (HO-1), a rate-limiting enzyme involved in the degradation of heme, is induced in response to a wide range of stress conditions. HO-1 exerts antiviral activity against a broad range of viruses, including the Hepatitis C virus, the human immunodeficiency virus, and the dengue virus by inhibiting viral growth. It has been reported that HO-1 displays antiviral activity against the Zika virus (ZIKV) but the mechanisms of viral inhibition remain largely unknown. Using a ZIKV RNA replicon with the Green Fluorescent Protein (GFP) as a reporter protein, we were able to show that HO-1 expression resulted in the inhibition of viral RNA replication. Conversely, we observed a decrease in HO-1 expression in cells replicating the ZIKV RNA replicon. The study of human cells infected with ZIKV showed that the HO-1 expression level was significantly lower once viral replication was established, thereby limiting the antiviral effect of HO-1. Our work highlights the capacity of ZIKV to thwart the anti-replicative activity of HO-1 in human cells. Therefore, the modulation of HO-1 as a novel therapeutic strategy against ZIKV infection may display limited effect.

CGS 26303 Upregulates mRNA Expression of Heme Oxygenase-1 in Brain Tissue of Rats Subjected to Experimental Subarachnoid Hemorrhage

2004 ◽  
Vol 44 (Supplement 1) ◽  
pp. S474-S478 ◽  
Author(s):  
Chun-Po Yen ◽  
Shih-Chieh Chen ◽  
Tze-Kan Lin ◽  
Shu-Chuan Wu ◽  
Chao-Yuah Chang ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Mrna Expression ◽  
Brain Tissue ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Experimental Subarachnoid Hemorrhage

Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage

2003 ◽  
Vol 99 (2) ◽  
pp. 383-390 ◽  
Author(s):  
Gen Kusaka ◽  
Hitoshi Kimura ◽  
Ikuyo Kusaka ◽  
Eddie Perkins ◽  
Anil Nanda ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Mitogen Activated Protein Kinase ◽  
Src Tyrosine Kinase ◽  
Content Type ◽  
Upstream Regulator ◽  
Src Inhibitor ◽  
Basilar Arteries ◽  
Fine Print

Object. Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream regulator of MAPK, is involved in cerebral vasospasm. Methods. An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2—treated, and Src inhibitor damnacanthal—treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal. Conclusions. The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.

Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage

1996 ◽  
Vol 713 (1-2) ◽  
pp. 211-222 ◽  
Author(s):  
Paul Matz ◽  
Christopher Turner ◽  
Philip R. Weinstein ◽  
Stephen M. Massa ◽  
S.Scott Panter ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Rat Brain ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Experimental Subarachnoid Hemorrhage

Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage

1997 ◽  
Vol 3 (4) ◽  
pp. E8 ◽  
Author(s):  
John E. Wanebo ◽  
Hunter G. Louis ◽  
Adam S. Arthur ◽  
Jie Zhou ◽  
Neal F. Kassell ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Rabbit Model ◽  
Systemic Administration ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Cross Sectional ◽  
Basilar Arteries ◽  
The Mean

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ETA receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH. Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters. The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm2 in the control group to 0.106 mm2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm2 (78.1% of control) compared with the placebo BID value of 0.134 mm2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups. These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.

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