Heme Oxygenase-1 Gene Expression Attenuates Angiotensin II-Mediated DNA Damage in Endothelial Cells

Mazza, Francesco; Goodman, Alvin I.; Lombardo, Gabriella; Vanella, A.; Abraham, Nader G.

doi:10.1177/15353702-0322805-31

Cited by 46 publications

(38 citation statements)

References 38 publications

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“…19,43 Indeed, inhibition of HO by the addition of SnMP or in cells underexpressing HO-1 resulted in increased cellular heme and decreased generation of the antioxidant, bilirubin, and oxidative stress. 13, 41 Mazza et al 44 have shown that a decrease in HO-1 proteins increased DNA degradation. Thus, HO-1 expression could have a major influence on the biological effect of oxidant stress.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells

Abraham

Kushida

McClung

et al. 2003

Circulation Research

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143

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Abstract-Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (PϽ0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (PϽ0.001). Key Words: cell cycle Ⅲ oxidative stress Ⅲ superoxide anion production Ⅲ gene transfer Ⅲ heme oxygenase E xposure of endothelial cells to elevated glucose levels causes glucose oxidation, resulting in the generation of excess reactive oxygen species (ROS) in endothelial cells. A reduction in antioxidant reserves has been attributed to endothelial cell dysfunction in diabetes, even in patients with well-controlled glucose levels. 1-3 Hyperglycemia-mediated local formation of ROS is considered to be the major contributing factor to endothelial dysfunction, including abnormalities in cell cycling 1,4,5 and delayed replication, and these abnormalities can be reversed by antioxidant agents 6,7 and an increased expression of antioxidant enzymes. 8 Du et al 9 have demonstrated that hyperglycemia stimulates the induction of apoptosis in endothelial cells by a mechanism that involves the generation of ROS and superoxide anion formation. Moreover, high glucose conditions facilitated the susceptibility of various serum proteins to oxidation, which contributes to the inhibition of endothelial cell proliferation. 10 Wolf et al 11 have reported that high glucose stimulates mitogen-activated protein kinase, which was associated with an enhancement in p27 Kip1 protein and growth arrest.We have previously shown that overexpression of the human heme oxygenase-1 (HO-1) gene in rabbit and rat endothelial cells renders the cells resistant to oxidative stress-causing agents 12 and enhances cell growth 13,14 and angiogenesis, 15 which highlights the important metabolic and cytoprotective role of the HO-1 gene. 12,15-17 Inhibition of HO activity has been shown to exacerbate the inflammatory response in the arterial wall in animal models of atherosclerosis model. 18 HO-1 is expressed, under basal conditions, at low levels in endothelial cells 12,15,19,20 and can be induced in these cells in response to oxidants, including heme, H 2 O 2 , and tumor necrosis factor. [21][22][23] It is conceivable, then, that upregulation of HO activity could function to attenuate the glucosemediated inhibition of cell-cycle progression.The objectives of this study were to determine the effects of glucose on HO activity and the expression of HO-1 and HO-2 proteins and DNA distribution and to examine the role of heme metabolism by HO on cell-cycle progression. We also examined the effect of overexpression and un...

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells

Abraham

Kushida

McClung

et al. 2003

Circulation Research

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143

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“…Bilirubin, in low concentrations, scavenges ROS in vitro, reduces oxidant-induced cellular injury, and attenuates oxidative stress in vivo (34,141,142,183). The antioxidant and cytoprotective effects of bilirubin in attenuating ANG II-mediated DNA damage and cell death have been described (116). Recently, increased expression of HO-1 resulting in elevated levels of biliverdin/bilirubin has been shown to preserve vascular integrity and prevent EC death and sloughing (178), thus enhancing vascular repairs in diabetic rats (12,196).…”

Section: Bilirubin and Oxidative Stressmentioning

confidence: 99%

Heme oxygenase: the key to renal function regulation

Abraham

Cao

Sacerdoti

et al. 2009

American Journal of Physiology-Renal Physiology

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Heme oxygenase (HO) plays a critical role in attenuating the production of reactive oxygen species through its ability to degrade heme in an enzymatic process that leads to the production of equimolar amounts of carbon monoxide and biliverdin/bilirubin and the release of free iron. The present review examines the beneficial role of HO-1 (inducible form of HO) that is achieved by increased expression of this enzyme in renal tissue. The influence of the HO system on renal physiology, obesity, vascular dysfunction, and blood pressure regulation is reviewed, and the clinical potential of increased levels of HO-1 protein, HO activity, and HO-derived end products of heme degradation is discussed relative to renal disease. The use of pharmacological and genetic approaches to investigate the role of the HO system in the kidney is key to the development of therapeutic approaches to prevent the adverse effects that accrue due to an impairment in renal function.

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“…These include its substrate, heme (9, 10); oxidative stress (11,12); the signaling proteins nerve growth factor, tumor necrosis factor-␣, interleukin-1␤, and interferon-␥ (13-15); and phenolic compounds such as curcumin and caffeic acid (16). Many reports have demonstrated the potent antioxidant activity of the heme-derived metabolites generated by HO-1 catalysis (biliverdin and bilirubin) and the cytoprotective actions of carbon monoxide on vascular endothelium and nerve cells (17)(18)(19)(20). Moreover, both HO-1-deficient mice (21) and a human case of genetic HO-1 deficiency (22) exhibit a serious impairment of iron metabolism, leading to liver and kidney oxidative damage and inflammation.…”

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confidence: 99%

Regulation of Heme Oxygenase-1 Expression through the Phosphatidylinositol 3-Kinase/Akt Pathway and the Nrf2 Transcription Factor in Response to the Antioxidant Phytochemical Carnosol

Martı́n

Rojo

Salinas

et al. 2004

Journal of Biological Chemistry

658

427

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The phosphatidylinositol 3-kinase (PI3K)/Akt pathway elicits a survival signal against multiple apoptotic insults. In addition, phase II enzymes such as heme oxygenase-1 (HO-1) protect cells against diverse toxins and oxidative stress. In this work, we describe a link between these defense systems at the level of transcriptional regulation of the antioxidant enzyme HO-1. The herb-derived phenol carnosol induced HO-1 expression at both mRNA and protein levels. Luciferase reporter assays indicated that carnosol targeted the mouse ho1 promoter at two enhancer regions comprising the antioxidant response elements (AREs). Moreover, carnosol increased the nuclear levels of Nrf2, a transcription factor governing AREs. Electrophoretic mobility shift assays and luciferase reporter assays with a dominantnegative Nrf2 mutant indicated that carnosol increased the binding of Nrf2 to ARE and induced Nrf2-dependent activation of the ho1 promoter. While investigating the signaling pathways responsible for HO-1 induction, we observed that carnosol activated the ERK, p38, and JNK pathways as well as the survival pathway driven by PI3K. Inhibition of PI3K reduced the increase in Nrf2 protein levels and activation of the ho1 promoter. Expression of active PI3K-CAAX (where A is aliphatic amino acid) was sufficient to activate AREs. The use of dominant-negative mutants of protein kinase C and Akt1, two kinases downstream from PI3K, demonstrated a requirement for active Akt1, but not protein kinase C. Moreover, the long-term antioxidant effect of carnosol was partially blocked by PI3K or HO-1 inhibitors, further demonstrating that carnosol attenuates oxidative stress through a pathway that involves PI3K and HO-1.High levels of reactive oxygen species cause damage to cells and are involved in several human pathologies, including neurodegenerative disorders and cancer (1, 2). Therefore, the use of compounds with antioxidant properties may help prevent or alleviate diseases in which oxidative stress is a primary cause (3). Carnosol, a diterpene derived from the herb rosemary, is a representative member of a family of plant-derived phenols, which also include curcumin, carnosic acid, phenylethyl isothiocyanate, epigallocatechin gallate, and other green tea polyphenols. These bioactive phytochemicals exhibit Michael acceptor function and therefore behave as antioxidants (4). In addition, being themselves xenobiotic compounds, they activate a xenobiotic response in the target cells affecting the expression of phase II enzymes such as NAD(P)H:quinone oxidoreductase, aldoketoreductase, glutathione S-transferase, ␥-glutamylcysteine synthetase, glutathione synthetase, and heme oxygenase-1 (HO-1) 1 (5-7). Heme oxygenase isozymes (HO-1 and HO-2) catalyze the stepwise degradation of heme to release free iron and equimolar concentrations of carbon monoxide and the linear tetrapyrrole biliverdin, which is converted to bilirubin by the enzyme biliverdin reductase (8). The HO-1 isozyme is a phase II enzyme that is transcriptionally regulated by a large...

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Heme Oxygenase-1 Gene Expression Attenuates Angiotensin II-Mediated DNA Damage in Endothelial Cells

Cited by 46 publications

References 38 publications

Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells

Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells

Heme oxygenase: the key to renal function regulation

Regulation of Heme Oxygenase-1 Expression through the Phosphatidylinositol 3-Kinase/Akt Pathway and the Nrf2 Transcription Factor in Response to the Antioxidant Phytochemical Carnosol

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