Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent work has demonstrated that the brain has the capacity to synthesize impressive amounts of the gases nitric oxide (NO) and carbon monoxide (CO). There is growing evidence that these gaseous molecules function as novel neural messengers in the brain. This article reviews the pertinent literature concerning the putative role of NO and CO as critical neurotransmitters and biological mediators of the neuroendocrine axis. Abundant evidence is presented which suggests that NO has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus. NO potently stimulates GnRH secretion and also appears to mediate the action of one of the major transmitters controlling GnRH secretion, glutamate. Evidence is presented which suggests that NO stimulates GnRH release due to its ability to modulate the heme-containing enzyme, guanylate cyclase, which leads to enhanced production of the second messenger molecule, cGMP. A physiological role for NO in the preovulatory LH surge was also evidenced by findings that inhibitors and antisense oligonucleotides to nitric oxide synthase (NOS) attenuate the steroid-induced and preovulatory LH surge. CO may also play a role in stimulating GnRH secretion as heme molecules stimulate GnRH release in vitro, an effect which requires heme oxygenase activity and is blocked by the gaseous scavenger molecule, hemoglobin. Evidence is also reviewed which suggests that NO acts to restrain the hypothalamic-pituitary-adrenal (HPA) axis, as it inhibits HPA stimulation by various stimulants such as interleukin-1 beta, vasopressin, and inflammation. This effect fits a proinflammatory role of NO as it leads to suppression of the release of the anti-inflammatory corticosteroids from the adrenal. Although not as intensely studied as NO, CO has been shown to suppress stimulated CRH release and may also function to restrain the HPA axis. Evidence implicating NO in the control of prolactin and growth hormone secretion is also reviewed and discussed, as is the possible role of NO acting directly at the anterior pituitary. Taken as a whole, the current data suggest that the diffusible gases, NO and CO, act as novel transmitters in the neuroendocrine axis and mediate a variety of important neuroendocrine functions.
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PMID:Gaseous transmitters and neuroendocrine regulation. 920

Both the cytokine, interleukin-1 (IL-1), and the gaseous neurotransmitters, nitric oxide (NO) and carbon monoxide (CO), have been implicated in the control of neuroendocrine functions, such as the release of CRH and luteotropic hormone-releasing hormone from the hypothalamus. Though increased levels of IL-1 in this brain region are unambiguously associated with enhanced CRH and reduced luteotropic hormone-releasing hormone release, the net effects of the two gases are still unclear, but in vivo and in vitro evidence suggests that the generation of NO and CO within the hypothalamus might counteract the stimulatory effects of IL-1 and bacterial lipopolysaccharide on the neuroendocrine stress axis. In this study, we have investigated the effects of NO and CO on the release of immunoreactive (ir)-IL-1beta from the rat hypothalamus in vitro. It was observed that the NO donor, sodium nitroprusside (SNP), stimulates ir-IL-1beta release under basal conditions, whereas the increase in CO levels obtained with hemin, the CO precursor through the heme oxygenase pathway, has no effect on basal ir-IL-1beta release but inhibits release stimulated by high K+ concentrations. The opposite effects of the two gases on cytokine release seemed to be caused by the activation of different signaling pathways, because: 1) SNP, but not CO-saturated solutions, is able to increase cyclic GMP levels in hypothalamic tissue; 2) CO-saturated solutions increase PGE2 production and release from the hypothalamic explants, whereas SNP has no effect; 3) SNP-stimulated ir-IL-1beta release is counteracted by a selective inhibitor of soluble guanylyl cyclase, LY 83583, but not by a cyclooxygenase inhibitor, indomethacin; and 4) conversely, indomethacin, but not LY 83583, reverses the inhibitory effect of hemin on K+-stimulated ir-IL-1beta release. It is concluded that NO and CO signal in the rat hypothalamus via the activation of soluble guanylyl cyclase and cyclooxygenase, respectively.
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PMID:The generation of nitric oxide and carbon monoxide produces opposite effects on the release of immunoreactive interleukin-1beta from the rat hypothalamus in vitro: evidence for the involvement of different signaling pathways. 949 35

Although two-way communication between the hypothalamus and the immune system in now well established, particularly for the hypothalamo-pituitary-adrenal axis, the role of the gaseous neurotransmitters nitric oxide (NO) and carbon monoxide (CO) is much less well understood in terms of hypothalamic function. These agents are an important part of the peripheral inflammatory response; and their synthetic enzymes, NO synthase (NOS) and heme oxygenase (HO), respectively, have been localized to the hypothalamic PVN and SON. The induced generation of both NO and CO leads to the suppression of CRH and vasopressin, the major stimulators of the HPA. Thus, the addition of hemin to hypothalamic explants is maximally active at 1 microM in attenuating the release of CRH and vasopressin, and this dose is also most effective in generating biliverdin and associated CO. CO generation is also able to stimulate cyclooxygenase to produce prostaglandin E2, an established intermediary in the cytokine-stimulated activation of the HPA. Finally, inducible NOS mRNA is specifically induced in the hypothalalmus in response to endotoxin, in parallel to interleukin-1. These data provide increasing evidence in favor of NO and CO as counterregulatory agents in the HPA response to immune activation.
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PMID:Acute and subacute effects of endotoxin on hypothalamic gaseous neuromodulators. 962 53

The gene expression and synthesis of both constitutive and inducible heme oxygenase (HO) isoforms have been recently described in human placental cells, but the functional role(s) of this biochemical pathway in placental physiology and pathology is still unclear. In the present study, we have investigated whether HO activity is involved in the control of CRH secretion from trophoblast cells. Fluctuations in HO activity were induced in primary cultures of human trophoblast cells using well-known activators and inhibitors of HO, and the subsequent changes in CRH secretion were monitored measuring CRH immunoreactivity released into the incubation medium. It was found that the increase in HO activity induced by hemin or cobalt chloride (CoCl(2)) was associated with parallel significant increases in CRH release. This effect was probably caused by the gaseous HO end-product, carbon monoxide (CO), because it was blocked by the HO inhibitor tin-mesoporphyrin-9, but it was not mimicked by stable HO end-products, biliverdin and bilirubin. We have also investigated whether stimulation of CRH release induced by HO was mediated by the cyclooxygenase (COX) pathway. Indeed, hemin also caused significant increases in PGE2 release in this experimental paradigm. However, CoCl(2), which also enhances CRH release, had no stimulatory effect and actually inhibited PG secretion; moreover, a nonselective COX inhibitor, indomethacin, failed to counteract hemininduced CRH release. Taken collectively, these findings suggested that modulation of CRH secretion by the HO-CO system occurs through a mechanism independent of COX activity.
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PMID:Evidence for a functional link between the heme oxygenase-carbon monoxide pathway and corticotropin-releasing hormone release from primary cultures of human trophoblast cells. 1123 18