Human Heme Oxygenase-1 Gene Transfer Lowers Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats

Sabaawy, Hatem E.; Zhang, Fan; Nguyen, Xuandai; ElHosseiny, Abdelmonem; Nasjletti, Alberto; Schwartzman, Michal Laniado; Dennery, Phyllis A.; Kappas, Attallah; Abraham, Nader G.

doi:10.1161/01.hyp.38.2.210

Cited by 141 publications

(98 citation statements)

References 32 publications

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“…For example, the administration of HO-1 inducers is known to lower blood pressure and enhance tissue growth in spontaneously hypertensive rats (31), whereas the administration of HO-1 inhibitors produces systemic vasoconstriction (32)(33)(34). These effects have been correlated with the levels of cellular heme and one of the end products of heme catabolism, CO. An important role for HO in the control of vascular tone and blood pressure and in the regulation of growth is indicated by these findings.…”

Section: Discussionmentioning

confidence: 99%

“…The effect, however, is short-lasting (2 to 4 weeks). In contrast, retroviral gene transfer offers long lasting expression of the gene being carried (31,38). The availability of retroviral vectors expressing HHO-1 S and AS thus offers a means to assess the long-term consequences on physiological processes of sustained alterations in human HO activity.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs

Quan

Yang

Abraham

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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C ellular levels of heme are regulated by the rates of its synthesis and degradation. Heme catabolism occurs by oxidative cleavage of the ␣-methene bridge of the tetrapyrrole, eventually leading to the formation of equimolar amounts of biliverdin and CO and the release of the contained iron atom (1, 2). Biliverdin is then rapidly reduced to form bilirubin (3, 4). The heme oxygenase (HO) system controls the rate-limiting step in heme catabolism (5). To date, three HO isoforms (HO-1, HO-2, and HO-3) have been identified that catalyze this reaction (6-8). HO-1 is a 32-kDa heat shock protein (9-11) that is inducible by numerous noxious stimuli (12-17). HO-2 is a constitutively synthesized 36-kDa protein that is abundant in brain and testis (6). HO-3 is related to HO-2, but is the product of a different gene, and its ability to catalyze heme degradation is much less than that of .Overexpression of HO-1 can lead to hyperbilirubinemia in humans with certain hepatic disorders, especially patients in whom bilirubin disposition is impaired for developmental or genetic reasons, i.e., in newborns and in patients with the Crigler-Najjar type I syndrome. Pharmacological agents such as the inhibitor of HO, tin mesoporphyrin, can inhibit HO activity significantly and have been shown to be highly effective in single dose in controlling hyperbilirubinemia in newborns and other patients (19-23). However, such agents can exert only transient control of the activity of HO-1. Further, the long-term overexpression or underexpression of human HO-1 (HHO-1) would have considerable experimental value in elucidating the role of the enzyme in physiological and pathological processes.The objective of this study was to examine the feasibility of using the retrovirus-mediated transfer of an HHO-1 sense (S) and antisense (AS) orientation sequence under the control of the HHO-1 promoter to regulate endogenous HO-1 expression and function and thus permit development of a gene transfer technology to regulate the rate of heme catabolism over the long term.Our data demonstrate that selective delivery of the HHO-1 gene in AS orientation into human endothelial cells results in an attenuation of HHO-1 protein leading to a decrease in the rate of catabolism of cellular heme and that this effect is brought about without altering endogenous HO-2 protein. Thus, by the use of the retroviral HO-1 AS methodology it is possible to envisage prolonged down-regulation of the rate of heme catabolism to its degradation product bilirubin in clinical or experimental circumstances where this might prove useful. Materials and MethodsCell Culture Conditions. The amphotropic retroviral packaging cell line PA317 (American Type Culture Collection) or PT67 (CLON-TECH) was used for the generation of replication-deficient recombinant retroviruses. PA317 and PT67 cells were grown in DMEM (GIBCO͞BRL, Grand Island, NY) supplemented with 10% heatinactivated FBS. NIH 3T3 fibroblasts were cultured in DMEM with 10% calf serum. Human dermal microvessel endothelial cells (HMEC-1 cells...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs

Quan

Yang

Abraham

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly, the first human case of HO-1 deficiency exhibited severe growth retardation, and the patient died at a young age (Yachie et al, 1999). More recently, Sabaawy et al (2001) found that the systemic administration of a retrovirus containing the human HO-1 gene to young rats results in a marked increase in body weight and size relative to control animals. The increase in somatic growth is proportionate and is not associated with an increase in food intake.…”

Section: Ho-1 and Growth Regulationmentioning

confidence: 97%

“…Similarly, adenovirus-mediated transfer of HO-1 to arteries significantly attenuates the development of atherosclerosis in apoE null mice and graft arteriosclerosis in a rat model of chronic allogeneic aorta rejection (Juan et al, 2001;Bouche et al, 2002). In addition, upregulation of HO-1 by heme analogues or by retroviral gene delivery lowers blood pressure in spontaneously hypertensive rats (Levere et al, 1990;Johnson et al, 1995;Sabaawy et al, 2001) while the targeted overexpression of HO-1 in lungs protects against pulmonary vessel wall hypertrophy induced by hypoxia (Minamino et al, 2001).…”

Section: Ho-1 As a Therapeutic Target In Vascular Diseasementioning

confidence: 99%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

143

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme to carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although interest in HO-1 originally centered on its heme-degrading function, recent findings indicate that HO-1 exerts other biologically important actions. Emerging evidence suggests that HO-1 plays a critical role in growth regulation. Deletion of the HO-1 gene or inhibition of HO-1 activity results in growth retardation and impaired fetal development, whereas HO-1 overexpression increases body size. Although the mechanisms responsible for the growth promoting properties of HO-1 are not well established, HO-1 can indirectly influence growth by regulating the synthesis of growth factors and by modulating the delivery of oxygen or nutrients to specific target tissues. In addition, HO-1 exerts important effects on critical determinants of tissue size, including cell proliferation, apoptosis, and hypertrophy. However, the actions of HO-1 are highly variable and may reflect a role for HO-1 in maintaining tissue homeostasis. Considerable evidence supports a crucial role for HO-1 in blocking the growth of vascular smooth muscle cells (SMCs). This antiproliferative effect of HO-1 is mediated primarily via the release of CO, which inhibits vascular SMC growth via multiple pathways. Pharmacologic or genetic approaches targeting HO-1 or CO to the blood vessel wall may represent a promising, novel therapeutic approach in treating vascular proliferative disorders.

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“…Heme oxygenase-1 (HO-1) is an inducible protein whose expression is increased several fold in response to a variety of cellular stresses and stimuli including ischemia [3] hypoxia [4], oxidative stress [5] and inflammatory cytokines [6], suggesting an important role for this enzyme in tissue protection. Several studies have shown that HO-1 over-expression protects against ischemia/reperfusion injury in a variety of tissues including the myocardium [7][8][9][10][11]. Conversely, reduced HO-1 levels increase susceptibility to injury in a variety of stress conditions.…”

Section: Introductionmentioning

confidence: 99%

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

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Heme-oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent in various models of ischemia/reperfusion (I/R) injury. However, the role of downstream mediators involved in HO-1 induced cytoprotection is not clear. In the current study we investigated the role of biliverdin reductase, an enzyme involved in the conversion of HO-1 derived biliverdin into bilirubin and the PI3K/Akt pathway in mediating the cytoprotective effects of HO-1 against hypoxia and reoxygenation (H/R) injury in vitro and in vivo. H9c2 cardiomyocytes were transfected with a plasmid expressing HO-1 or LacZ and exposed to 24 hours of hypoxia followed by 12 hours of reoxygenation. At the end of reoxygenation, reactive oxygen species generation was determined using CM-H 2 DCFDA dye and apoptosis was assessed by TUNEL, caspase activity and Bad phosphorylation. p85 and Akt phosphorylation were determined using cell based ELISA and phospho-specific antibodies, respectively. HO-1 overexpression increased phosphorylation of the regulatory subunit of the PI3K (p85α) and downstream effector Akt in H9c2 cells, leading to decreased ROS and apoptosis. Furthermore, cardiac specific HO-1 expression increased basal phosphorylated Akt levels and decreased infarct size in response to LAD ligation and release induced I/R injury. Conversely, PI3K inhibition reversed the effects of HO-1 on Akt phosphorylation, cell death and infarct size. In addition, knockdown of biliverdin reductase (BVR) expression with siRNA attenuated HO-1 induced Akt phosphorylation and increased H/R-induced apoptosis of H9c2 cells. Co-immunoprecipitation revealed protein-protein interaction between BVR and the phosphorylated p85 subunit of the PI3 kinase. Taken together, these results suggest that the enzyme biliverdin reductase plays an important role in mediating cytoprotective effects of HO-1. This effect is mediated, at least in part, via activation of the PI3K/Akt pathway.

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Human Heme Oxygenase-1 Gene Transfer Lowers Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats

Cited by 141 publications

References 32 publications

Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs

Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

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