Expression and Regulation of Heme Oxygenase Isozymes in the Developing Mouse Cortex

Department of Pediatrics , Stanford University, Palo Alto, California, United States
Pediatric Research (Impact Factor: 2.31). 12/2006; 60(5):518-23. DOI: 10.1203/01.PDR.0000242374.21415.f5
Source: PubMed


Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, plays a role in neonatal jaundice. Understanding the regulation of the developmental expression patterns of the two HO isozymes, HO-1 and HO-2, is essential for targeting HO to control pathologic jaundice, and uncovering the fundamental role that they play in mammalian development. Here we characterized the ontogeny of HO-1 and HO-2 expression in the developing mouse cortex by in vivo bioluminescence imaging, quantitative RT-PCR, and Western blot. HO-2, the predominant isoform in the adult cortex, was relatively stable throughout all ages. HO-1 was observed to be progressively down-regulated in an age-related manner. HO-1 expression in the adult cortex was also the lowest among the eight adult tissues analyzed. Because there is a 283-bp CpG island region in the HO-1 promoter, we hypothesized that methylation of the island is responsible for the age-related HO-1 down-regulation in the cortex. Methylation status was assessed using regular and quantitative methylation-specific PCR and the CpG island was found to be hypomethylated at all ages. Therefore, we conclude that HO-1 gene expression in the cortex is developmentally-regulated and that methylation of the HO-1 CpG island is not associated with the down-regulation of the gene.

Download full-text


Available from: Christopher H Contag, May 20, 2014
14 Reads
  • Source
    • "On the other hand, HO-2 has been considered as the constitutive isoform. High expression is observed in testis, brain, and endothelial and smooth cells from cerebral vessels [9] [10]. HO-2 is the abundant isoform in rat adult brain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hemeoxygenase (HO) system is responsible for cellular heme degradation to biliverdin, iron, and carbon monoxide. Two isoforms have been reported to date. Homologous HO-1 and HO-2 are microsomal proteins with more than 45% residue identity, share a similar fold and catalyze the same reaction. However, important differences between isoforms also exist. HO-1 isoform has been extensively studied mainly by its ability to respond to cellular stresses such as hemin, nitric oxide donors, oxidative damage, hypoxia, hyperthermia, and heavy metals, between others. On the contrary, due to its apparently constitutive nature, HO-2 has been less studied. Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function. HO-2 presents particular characteristics that made it a unique protein in the HO system. Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform. We summarize information on gene description, protein structure, and catalytic activity of HO-2 and particular facts such as its cellular impact and activity regulation. Finally, we call attention on the role of HO-2 in oxygen sensing, discussing proposed hypothesis on heme binding motifs and redox/thiol switches that participate in oxygen sensing as well as evidences of HO-2 response to hypoxia.
    Oxidative medicine and cellular longevity 07/2014; 2014(10):604981. DOI:10.1155/2014/604981 · 3.36 Impact Factor
  • Source
    • "In the adult brain, HO-2 is the isoenzyme predominantly expressed. In contrast, HO-1 expression in the brain is developmentally regulated, being highest in the early gestational ages and progressively decreasing during the perinatal period to adulthood (Zhao et al., 2006). The constitutive HO-2 isoform is important in the maintenance of neuronal function, whereas HO-1 is believed to play a protective role (Snyder et al., 1998; Maines, 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.
    Frontiers in Pharmacology 04/2012; 3:68. DOI:10.3389/fphar.2012.00068 · 3.80 Impact Factor
  • Source
    • "For this purpose often transgenic animals are generated expressing luciferase either ubiquitously or under the control of a regulated promoter. As bioluminescence will occur only when the controlling promoter is active, this technique enables the monitoring of spatiotemporal changes of protein expression in vivo e.g., as applied for analysis of the heme oxygenase-1 that plays a key role in development and where disregulation is often associated with jaundice in neonates [84, 85]. Transgenic mice expressing luciferase under the control of a lobe-specific promoter were used to investigate the early onset of retinoblastoma [86] or to generate luciferase expressing haematopoietic stem cells used for the visualization of leukemogenesis after transplantation in bone-marrow-depleted mice [87]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue.
    Pediatric Radiology 02/2011; 41(2):161-75. DOI:10.1007/s00247-010-1907-0 · 1.57 Impact Factor
Show more