Pharmacological and Clinical Aspects of Heme Oxygenase

Abraham, Nader G.; Kappas, Attallah

doi:10.1124/pr.107.07104

Cited by 1,012 publications

(1,033 citation statements)

References 602 publications

(598 reference statements)

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“…To test whether heme degradation is regulated by the circadian clock, we analyzed transcript and activity levels of Ho-1, the major heme-degrading enzyme in peripheral tissues 9 . In regular 6-h intervals over the course of two consecutive days, we harvested livers from mice kept in constant darkness and determined Ho-1 transcript levels by quantitative RT-PCR.…”

Section: Heme Degradation Is Regulated By the Circadian Clockmentioning

confidence: 99%

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

Klemz

Reischl

Wallach

et al. 2016

Nat Struct Mol Biol

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Section: Heme Degradation Is Regulated By the Circadian Clockmentioning

confidence: 99%

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

Klemz

Reischl

Wallach

et al. 2016

Nat Struct Mol Biol

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“…1 Endogenously produced CO has cytoprotective functions in the cardiovascular system that include antiapoptotic, antioxidant, and antiinflammatory influences. [1][2][3][4][5] Gaseous CO, administered at low concentrations, provides an effective treatment for diseases characterized by oxidative stress and inflammation. 1,5 The effects of gaseous CO can be reproduced by CO donors, termed CO-releasing molecules (CORMs).…”

Section: Introductionmentioning

confidence: 99%

Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

Liu

Fedinec

Leffler

et al. 2014

J Cereb Blood Flow Metab

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Cerebral blood flow dysregulation caused by oxidative stress contributes to adverse neurologic outcome of seizures. A carbon monoxide (CO) donor CORM-A1 has antioxidant and cytoprotective properties. We investigated whether enteral supplements of CORM-A1 can improve cerebrovascular outcome of bicuculline-induced seizures in newborn piglets. CORM-A1 (2 mg/kg) was given to piglets via an oral gastric tube 10 minutes before or 20 minutes after seizure onset. Enteral CORM-A1 elevated CO in periarachnoid cerebrospinal fluid and produced a dilation of pial arterioles. Postictal cerebral vascular responses to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested 48 hours after seizures by intravital microscopy. The postictal responses of pial arterioles to bradykinin, glutamate, the AMPA receptor agonist quisqualic acid, ADP, and heme were greatly reduced, suggesting that seizures cause injury to endothelial and astrocyte components of the neurovascular unit. In contrast, in the two groups of piglets receiving enteral CORM-A1, the postictal cerebral vascular responsiveness to these dilators was improved. Overall, enteral supplements of CORM-A1 before or during seizures offer a novel effective therapeutic option to deliver cytoprotective mediator CO to the brain, reduce injury to endothelial and astrocyte components of cerebral blood flow regulation and to improve the cerebrovascular outcome of neonatal seizures.

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“…HO-1 was targeted in these experiments because its enzymatic endproducts, bilirubin and carbon monoxide, are antiapoptotic, antioxidative, antiinflammatory, and proangiogenic [1,2,10]. Additionally, HO-1 activation has been shown to enhance resistance against sepsis [7,19].…”

Section: Discussionmentioning

confidence: 99%

“…To expedite transition to the clinic, drugs in current use that are known to activate the nrf2/HO-1 pathway [1], although with less specificity, might be substituted for CoPP in future trials. Examples would include the statins and the phosphodiesterase-5 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Can Cytoprotective Cobalt Protoporphyrin Protect Skeletal Muscle and Muscle-derived Stem Cells From Ischemic Injury?

Wilson

Welikson

Luo

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Extremity trauma is the most common injury seen in combat hospitals as well as in civilian trauma centers. Major skeletal muscle injuries that are complicated by ischemia often result in substantial muscle loss, residual disability, or even amputation, yet few treatment options are available. A therapy that would increase skeletal muscle tolerance to hypoxic damage could reduce acute myocyte loss and enhance preservation of muscle mass in these situations. Questions/purposes In these experiments, we investigated (1) whether cobalt protoporphyrin (CoPP), a pharmacologic inducer of cytoprotective heme oxygenase-1 (HO-1), would upregulate HO-1 expression and activity in skeletal muscle, tested in muscle-derived stem cells (MDSCs); and (2) whether CoPP exposure would protect MDSCs from cell death during in vitro hypoxia/reoxygenation. Then, using an in vivo mouse model of hindlimb ischemia/reperfusion injury, we examined (3) whether CoPP pharmacotherapy would reduce skeletal muscle damage when delivered after injury; and (4) whether it would alter the host inflammatory response to injury. Methods MDSCs were exposed in vitro to a single dose of 25 lL CoPP and harvested over 24 to 96 hours, assessing HO-1 protein expression by Western blot densitometry and HO-1 enzyme activity by cGMP levels. To generate hypoxia/reoxygenation stress, MDSCs were treated in vitro with phosphate-buffered saline (vehicle), CoPP, or CoPP plus an HO-1 inhibitor, tin protoporphyrin (SnPP), and then subjected to 5 hours of hypoxia (\ 0.5% O 2 ) followed by 24 hours of reoxygenation and evaluated for apoptosis. In vivo, hindlimb ischemia/reperfusion injury was produced in mice by unilateral 2-hour tourniquet application followed by 24 hours of reperfusion. In three postinjury treatment groups (n = 7 mice/group), CoPP was administered intraperitoneally during ischemia, at the onset of reperfusion, or 1 hour later. Two control groups of mice with the same injury received phosphatebuffered saline (vehicle) or the HO-1 inhibitor, SnPP. Myocyte damage in the gastrocnemius and tibialis anterior muscles was determined by uptake of intraperitoneally This work was funded by USAMRMC Award W81XWH-07-01-0246 (MDA) and USAMRMC Award W81XWH-10-01-0789 (MDA Results In MDSCs, a single exposure to CoPP increased HO-1 protein expression and enzyme activity, both of which were sustained for 96 hours. CoPP treatment of MDSCs reduced apoptotic cell populations by 55% after in vitro hypoxia/reoxygenation injury (from a mean of 57.3% apoptotic cells in vehicle-treated controls to 25.7% in CoPP-treated cells, mean difference 31.6%; confidence interval [CI], 28.1-35.0; p \ 0.001). In the hindlimb ischemia/reperfusion model, CoPP delivered during ischemia produced a 38% reduction in myocyte damage in the gastrocnemius muscle (from 86.4% ± 7% EBD + myofibers in vehicle-treated, injured controls to 53.2% EBD + in CoPP-treated muscle, mean difference 33.2%; 95% CI, 18.3, 48.4; p \ 0.001). A 30% reduction in injury to the gastrocnemius was seen with drug...

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Pharmacological and Clinical Aspects of Heme Oxygenase

Cited by 1,012 publications

References 602 publications

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

Can Cytoprotective Cobalt Protoporphyrin Protect Skeletal Muscle and Muscle-derived Stem Cells From Ischemic Injury?

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