Heme-oxygenase induction inhibits arteriolar thrombosis in vivo: Effect of the non-substrate inducer cobalt protoporphyrin

Johns, Douglas G.; Zelent, Dorothy; Ao, Zhaohui; Bradley, Benjamin T.; Cooke, Alexandra E; Contino, Lisa C.; Hu, Erding; Douglas, Stephen A.; Jaye, Michael

doi:10.1016/j.ejphar.2008.12.030

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…Cobalt Protoporphyrin (CoPP) has been shown to have considerable pharmacological benefit in models of diabetes-linked vascular and renal damage [42]–[45], Ang II mediated hypertension [46], [47], renovascular hypertension [48], arterial thrombosis [49] and other oxidative stress-mediated pathologies. Inhibition of Bach1 itself has been suggested to be of benefit in diseases such as non-alcoholic steatohepatitis [50] and insulin resistance [51].…”

Section: Discussionmentioning

confidence: 99%

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

Attucks¹,

Jasmer

Hannink

et al. 2014

PLoS ONE

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Oxidative stress is generated by reactive oxygen species (ROS) produced in response to metabolic activity and environmental factors. Increased oxidative stress is associated with the pathophysiology of a broad spectrum of inflammatory diseases. Cellular response to excess ROS involves the induction of antioxidant response element (ARE) genes under control of the transcriptional activator Nrf2 and the transcriptional repressor Bach1. The development of synthetic small molecules that activate the protective anti-oxidant response network is of major therapeutic interest. Traditional small molecules targeting ARE-regulated gene activation (e.g., bardoxolone, dimethyl fumarate) function by alkylating numerous proteins including Keap1, the controlling protein of Nrf2. An alternative is to target the repressor Bach1. Bach1 has an endogenous ligand, heme, that inhibits Bach1 binding to ARE, thus allowing Nrf2-mediated gene expression including that of heme-oxygenase-1 (HMOX1), a well described target of Bach1 repression. In this report, normal human lung fibroblasts were used to screen a collection of synthetic small molecules for their ability to induce HMOX1. A class of HMOX1-inducing compounds, represented by HPP-4382, was discovered. These compounds are not reactive electrophiles, are not suppressed by N-acetyl cysteine, and do not perturb either ROS or cellular glutathione. Using RNAi, we further demonstrate that HPP-4382 induces HMOX1 in an Nrf2-dependent manner. Chromatin immunoprecipitation verified that HPP-4382 treatment of NHLF cells reciprocally coordinated a decrease in binding of Bach1 and an increase of Nrf2 binding to the HMOX1 E2 enhancer. Finally we show that HPP-4382 can inhibit Bach1 activity in a reporter assay that measures transcription driven by the human HMOX1 E2 enhancer. Our results suggest that HPP-4382 is a novel activator of the antioxidant response through the modulation of Bach1 binding to the ARE binding site of target genes.

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Section: Discussionmentioning

confidence: 99%

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

Attucks¹,

Jasmer

Hannink

et al. 2014

PLoS ONE

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“…Cobaltic protoporphyrin IX (CoPP), or hemin, has been shown to strongly induce HO-1 expression both in vivo and in vitro (15). Hemin promotes proliferation and differentiation in endothelial progenitor cells (16) and erythroid differentiation in human myeloid leukemia cells (17).…”

mentioning

confidence: 99%

The Role of Heme Oxygenase-1 in the Proliferation and Odontoblastic Differentiation of Human Dental Pulp Cells

Kim

Min

Ryu

et al. 2010

Journal of Endodontics

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“…In this model, time to thrombosis was shown to be sensitive to alteration in coagulation factors, platelets, and endothelial function (Westrick et al , 2007). The mechanism by which SCD protects against early occlusive thrombus formation is unclear but could also be related to HMOX1, because deficiency of HMOX1 is prothrombotic in this model (Johns et al , 2009; Fei et al , 2012) while overexpression of HMOX1 is protective against thrombosis (Lindenblatt et al , 2004). As HMOX1 has been shown to be upregulated in SCD leucocytes and proposed to mediate a compensatory response to repetitive vascular injury in SCD (Jison et al , 2004), we tested the effect of SCD or WT leucocyte infusions into recipient WT mice.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical protection from atherosclerosis and thrombosis in a mouse model of sickle cell disease

et al. 2013

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Summary Sickle cell disease (SCD) is associated with vascular complications including premature stroke. The role of atherothrombosis in these vascular complications is unclear. To determine the effect of SCD on atherosclerosis and thrombosis, mice with SCD along with controls were generated by transplantation of bone marrow from mice carrying the homozygous sickle cell mutation (Hbbhβs/hβs) or wild-type mice (Hbb+/+) into C57BL6/J or apolipoprotein E deficient (Apoe−/−) recipient mice. At the time of sacrifice, 23–28 weeks following bone marrow transplantation, anaemia, reticulocytosis, and splenomegaly were present in mice receiving Hbbhβs/hβs bone marrow compared with control mice. Analysis of atherosclerosis involving the aortic root revealed reduced atherosclerotic lesion area with reduced macrophage content and increased collagen content in Apoe−/−, Hbbhβs/hβs mice compared to Apoe−/−, Hbb+/+ mice. In a carotid thrombosis model, the time to thrombosis was prolonged in Hbbhβs/hβs mice compared to Hbb+/+ mice. This apparent protective effect of SCD on atherosclerosis and thrombosis was diminished by inhibition of heme oxygenase-1 (HMOX1) using zinc protoporphyrin IX. We conclude that SCD in mice is paradoxically protective against atherosclerosis and thrombosis, highlighting the complexity of vascular events in SCD. This protective effect is at least partially mediated by induction of HMOX1.

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Heme-oxygenase induction inhibits arteriolar thrombosis in vivo: Effect of the non-substrate inducer cobalt protoporphyrin

Cited by 9 publications

References 25 publications

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

The Role of Heme Oxygenase-1 in the Proliferation and Odontoblastic Differentiation of Human Dental Pulp Cells

Paradoxical protection from atherosclerosis and thrombosis in a mouse model of sickle cell disease

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