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_5 label "Selventa" provenance.
_4 value "Overexpression of HO-1 can lead to hyperbilirubinemia in humans with certain hepatic disorders especially in patients in whom bilirubin disposition is impaired for developmental or genetic reasons, e.g., in newborns and in patients with the Crigler-Najjar Type I syndrome (Kappas et al., 1993). Drummond and colleagues have shown that pharmacological agents such as the inhibitor of HO, stannic mesoporphyrin, can inhibit HO activity significantly and is highly effective in a single dose in controlling hyperbilirubinemia (Martinez et al., 2001) (personal communication). However, such agents can exert only transient control of the activity of HO-1. Furthermore, the long-term overexpression or inhibition of different HO isoforms would have considerable experimental value in elucidating the role of the enzyme in physiological and pathological processes. Quan et al. (2001) examined the feasibility of utilizing the retrovirus-mediated transfer of a human HO-1 (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 gene transfer technology to regulate the rate of heme catabolism over the long term (Quan et al., 2001). Their data demonstrate for the first time that selective delivery of the hHO-1 gene in antisense 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 using retroviral HO-1 antisense 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. Alternatively, inhibition of HO isoforms may be established using RNA interference techniques. In contrast, the development of gene transfer techniques has provided the opportunity to deliver a functional HO-1 gene and to evaluate the direct effects of this gene on, e.g., vascular functions. Using a retroviral vector, Sabaawy et al. (2001) established chimeric rats expressing the human HO-1 gene to study hypertension. Surprisingly, they observed that these rats, in addition to developing decreased blood pressure, grew significantly faster than rats lacking the hHO-1 gene, particularly during the first 12 weeks. Importantly, the increase in somatic growth associated with hHO-1 expression in rats was both proportionate and not associated with an increase in food intake. Interestingly, both human (Yachie et al., 1999) and mice (Poss and Tonegawa, 1997a) lacking the HO-1 gene display severe growth retardation. An alternative means of establishing HO isoform overexpression is the use of TAT-HO proteins. The fusion protein of HO-1 to an 11-amino acid cell-penetrating peptide from the human immunodeficiency virus TAT protein enables efficient HO-1 protein entry and proved to protect pancreatic -cells against TNF--mediated injury (Ribeiro et al., 2003). The importance of a fine balance of the heme-HO system is further underscored by accumulating data demonstrating that induction of HO-1 by gene transfer protects cells from hemoglobin/heme-mediated oxidative stress, leukocyte infiltration, and against a range of inflammatory complications, such as ischemia/reperfusion injury and hyperoxia-induced injury (Abraham et al., 1995b; Amersi et al., 1999; Yang et al., 1999). Moreover, it has recently been found that HO-1 gene transfer protects blood vessels from pathological vasoconstriction and excessive smooth muscle cell proliferation in animal models of arterial injury (Duckers et al., 2001). Furthermore, HO-1 transgenic mice are protected from hypoxia-induced inflammation and vascular dysfunction (Minamino et al., 2001). " provenance.
_4 wasQuotedFrom 12869663 provenance.
assertion hadPrimarySource 12869663 provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
assertion wasDerivedFrom _4 provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
large_corpus.bel authoredBy _5 provenance.
large_corpus.bel version "20131211" provenance.