RESUMO
Heme oxygenase (HO) enzymes are responsible for the main oxidative step in heme degradation, generating equimolar amounts of free iron, biliverdin and carbon monoxide. HO-1 is induced as a crucial stress response protein, playing protective roles in physiologic and pathological conditions, due to its antioxidant, anti-apoptotic and anti-inflammatory effects. The mechanisms behind HO-1-mediated protection are being explored by different studies, affecting cell fate through multiple ways, such as reduction in intracellular levels of heme and ROS, transcriptional regulation, and through its byproducts generation. In this review we focus on the interplay between HO-1 and immune-related signaling pathways, which culminate in the activation of transcription factors important in immune responses and inflammation. We also discuss the dual interaction of HO-1 and inflammatory mediators that govern resolution and tissue damage. We highlight the dichotomy of HO-1 in innate and adaptive immune cells development and activation in different disease contexts. Finally, we address different known anti-inflammatory pharmaceuticals that are now being described to modulate HO-1, and the possible contribution of HO-1 in their anti-inflammatory effects.
Assuntos
Imunidade Adaptativa , Heme Oxigenase (Desciclizante) , Imunidade Inata , Anti-Inflamatórios , Antioxidantes , Biliverdina , Monóxido de Carbono , Heme/metabolismo , Heme Oxigenase (Desciclizante)/fisiologia , Mediadores da Inflamação , Ferro , Espécies Reativas de Oxigênio , Fatores de TranscriçãoRESUMO
Resveratrol, a phytoalexin found in grapes and wine, exhibits antioxidant, anti-inflammatory, anti-aging and antitumor activities. Resveratrol also protects neurons and astrocytes in several neurological disease models. Astrocytes are responsible for modulating neurotransmitter systems, synaptic information, ionic homeostasis, energy metabolism, antioxidant defense and inflammatory response. In previous work, we showed that resveratrol modulates important glial functions, including glutamate uptake, glutamine synthetase activity, glutathione (GSH) levels and inflammatory response. Furthermore, astrocytes express toll-like receptors that specifically recognize lipopolysaccharide (LPS), which has been widely used to study experimentally inflammatory response. In this sense, LPS may stimulate pro-inflammatory cytokines release and oxidative stress. Moreover, there is interplay between these signals through signaling pathways such as NFκB, HO-1 and MAPK. Thus, here, we evaluated the effects of resveratrol on LPS-stimulated inflammatory response in hippocampal primary astrocyte cultures and the putative role of HO-1, p38 and ERK pathways in the protective effect of resveratrol. LPS increased the levels of TNF-α, IL-1ß, IL-6 and IL-18 and resveratrol prevented these effects. Resveratrol also prevented the oxidative and nitrosative stress induced by LPS as well as the decrease in GSH content. Additionally, we demonstrated the involvement of NFκB, HO-1, p38 and ERK signaling pathways in the protective effect of resveratrol, providing the first mechanistic explanation for these effects in hippocampal astrocytes. Our findings reinforce the neuroprotective effects of resveratrol, which are mainly associated with anti-inflammatory and antioxidant activities.
Assuntos
Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Células Cultivadas , Heme Oxigenase (Desciclizante)/fisiologia , Hipocampo/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Ratos , Ratos Wistar , ResveratrolRESUMO
Guanosine, a guanine-based purine, is an extracellular signaling molecule that is released from astrocytes and shows neuroprotective effects in several in vivo and in vitro studies. Our group recently showed that guanosine presents antioxidant properties in C6 astroglial cells. The heme oxygenase 1 signaling pathway is associated with protection against oxidative stress. Azide, an inhibitor of the respiratory chain, is frequently used in experimental models to induce oxidative and nitrosative stress. Thus, the goal of this study was to investigate the effect of guanosine on azide-induced oxidative damage in C6 astroglial cells. Azide treatment of these cells resulted in several detrimental effects, including induction of cytotoxicity and mitochondrial dysfunction, increased levels of reactive oxygen/nitrogen species, inducible nitric oxide synthase expression and NADPH oxidase, decreased glutamate uptake and EAAC1 glutamate transporter expression, decreased glutathione (GSH) levels, and decreased activities of glutamine synthetase (GS), superoxide dismutase and catalase (CAT). The treatment also increased nuclear factor-κB activation and the release of proinflammatory cytokines tumor necrosis factor α and IL-1ß. Guanosine strongly prevented these effects, protecting glial cells against azide-induced cytotoxicity and modulating glial, oxidative and inflammatory responses through the activation of the heme oxygenase 1 pathway. These observations reinforce and support the role of guanosine as an antioxidant molecule against oxidative damage. Guanosine protects against azide-induced oxidative damage in C6 astroglial cells. Azide-induced mitochondrial dysfunction (1); increased reactive oxygen species/reactive nitrogen species levels (2); decreased glutamate uptake (3), GS activity (4), GSH levels (5), and SOD (6) and CAT (7) activities; increased glutathione peroxidase (GPx) (8) and NADPH oxidase (9) activities and cellular superoxide levels (10); increased NF-κB activation (11), TNF-α and IL-1ß levels (12); and induced iNOS expression (13). Guanosine prevented these effects through the HO1 signaling pathway, thus our findings support the antioxidant effects of guanosine.
Assuntos
Astrócitos/enzimologia , Azidas/toxicidade , Guanosina/farmacologia , Heme Oxigenase (Desciclizante)/fisiologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Linhagem Celular , Células Cultivadas , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Pulmonary arterial hypertension is one of the most serious pathologies that can affect the 140 million people living at altitudes over 2500 m. The primary emphasis of this review is pulmonary artery hypertension in mammals (sheep and llamas) at high altitude, with specific focus on the heme oxygenase and carbon monoxide (HO-CO) system. We highlight the fact that the neonatal llama has neither pulmonary artery hypertension nor pulmonary vascular remodeling in the Andean altiplano. These neonates have an enhanced HO-CO system function, increasing the HO-1 protein expression and CO production by the pulmonary vessels, when compared to llamas raised at low altitude, or neonatal sheep raised at high altitude. The neonatal sheep has high altitude pulmonary artery hypertension in spite of enhancement of the NO system, with high eNOS protein expression and NO production by the lung. The gasotransmitters NO and CO are important in the regulation of the pulmonary vascular function at high altitudes in both high altitude acclimatized species, such as the sheep, and high altitude adapted species, such as the llama.
Assuntos
Aclimatação/fisiologia , Altitude , Monóxido de Carbono/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Heme Oxigenase (Desciclizante)/fisiologia , Fenômenos Fisiológicos Respiratórios , Animais , Animais Recém-Nascidos , Camelídeos Americanos , Feminino , Gravidez , OvinosRESUMO
The aim of the present study was to investigate the role of the spinal cord heme oxygenase (HO)-carbon monoxide (CO)-soluble guanylate cyclase (sGC)-cGMP pathway in nociceptive response of rats to the formalin experimental nociceptive model. Animals were handled and adapted to the experimental environment for a few days before the formalin test was applied. For the formalin test 50 microl of a 1% formalin solution was injected subcutaneously in the dorsal surface of the right hind paw. Following injections, animals were observed for 1 h and flinching behavior was measured as the nociceptive response. Thirty min before the test, rats were pretreated with intrathecal injections with the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is known to induce the HO pathway. Control animals were treated with vehicles. We observed a significant increase in nociceptive response of rats treated with ZnDPBG, and a drastic reduction of flinching nociceptive behavioral response in the heme-lysinate treated animals. Furthermore, the HO pathway seems to act via cGMP, since methylene blue (a sGC inhibitor) prevented the reduction of flinching nociceptive behavioral response caused by heme-lysinate. These findings strongly indicate that the HO pathway plays a spinal antinociceptive role during the formalin test, acting via cGMP.
Assuntos
Monóxido de Carbono/fisiologia , GMP Cíclico/fisiologia , Heme Oxigenase (Desciclizante)/fisiologia , Dor/fisiopatologia , Medula Espinal/fisiologia , Animais , Deuteroporfirinas/farmacologia , Heme/análogos & derivados , Heme/farmacologia , Lisina/análogos & derivados , Lisina/farmacologia , Masculino , Azul de Metileno/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The aim of the present study was to investigate the role of the peripheral heme oxygenase (HO)-carbon monoxide (CO) pathway on nociceptive response of rats to the formalin experimental model of pain. Animals were handled and adapted to the experimental environment for a few days before the formalin test was applied. For the formalin test, 50 microl of a 1% formalin solution was used and injected subcutaneously in the dorsal surface of the right hind paw. Following injections, animals were observed for 1 h, and flinching behavior was measured as the nociceptive response. Twenty minutes before the test rats were pretreated with podal injections with the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is known to induce the HO pathway. Control animals were treated with vehicles. We observed a significant increase on nociceptive response of rats treated with ZnDPBG, and a drastic reduction of flinching nociceptive behavioral response in the heme-lysinate and CO treated animals. Among the three different HO products, CO seems to account for the heme-lysinate effect because the injection of the gas attenuated the flinching response whereas biliverdine and deferoxanine (an iron chelator) failed to cause any significant change. Furthermore, CO seems to act via cGMP, since methylene blue (a soluble guanylate cyclase inhibitor) prevented the reduction of the flinching nociceptive behavioral response caused by heme-lysinate. These findings strongly indicate that CO is the HO pathway product that plays an antinociceptive role during the formalin test, acting via cGMP.
Assuntos
Monóxido de Carbono/fisiologia , GMP Cíclico/fisiologia , Heme Oxigenase (Desciclizante)/fisiologia , Medição da Dor , Dor/fisiopatologia , Transdução de Sinais , Animais , Biliverdina/farmacologia , Desferroxamina/farmacologia , Deuteroporfirinas/farmacologia , Heme/análogos & derivados , Heme/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Quelantes de Ferro/farmacologia , Lisina/análogos & derivados , Lisina/farmacologia , Masculino , Dor/induzido quimicamente , Ratos , Ratos WistarRESUMO
1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.
Assuntos
Monóxido de Carbono/fisiologia , Heme Oxigenase (Desciclizante)/fisiologia , Hipertensão Portal/fisiopatologia , Norepinefrina/farmacologia , Vasoconstritores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Monóxido de Carbono/antagonistas & inibidores , Feminino , Heme Oxigenase-1 , Hipertensão Portal/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/fisiologia , Ratos , Ratos WistarRESUMO
Platelet-derived growth factor (PDGF) is a multifunctional protein which is known to induce a febrile response when injected intracerebroventricularly. The gaseous neurotransmitters, nitric oxide (NO) and carbon monoxide (CO), are both known to exert thermoregulatory effects and to participate in lipopolysaccharide-induced fever. In this study, we investigated the role of NO and CO in the febrile response to PDGF-BB in rats. Intracerebroventricular (i.c.v.) injection of PDGF-BB produced a dose-dependent increase in body temperature. This increase in body temperature induced by PDGF-BB was exacerbated by N(G)-nitro-L-arginine methyl ester (L-NAME-a nonselective NO synthase inhibitor) and S-methyl-L-thiocitrulline treatment [SMTC-a neuronal NOS (nNOS) selective inhibitor], but not by aminoguanidine treatment [an inducible NOS (iNOS) selective inhibitor]. Zinc deuteroporphyrin 2,4-bis glycol treatment (ZnDPBG-a nonselective heme oxygenase (HO) blocker) did not affect PDGF-BB fever. Our data indicate that the NO but not the CO pathway participates in PDGF-BB fever. Furthermore, our data show that nNOS is the NOS isoform responsible for NO synthesis in this response.
Assuntos
Monóxido de Carbono/fisiologia , Citrulina/análogos & derivados , Febre/metabolismo , Lipopolissacarídeos , Óxido Nítrico/fisiologia , Fator de Crescimento Derivado de Plaquetas/fisiologia , Tioureia/análogos & derivados , Animais , Becaplermina , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Citrulina/farmacologia , Deuteroporfirinas/farmacologia , Inibidores Enzimáticos/farmacologia , Febre/induzido quimicamente , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/fisiologia , Isoenzimas/antagonistas & inibidores , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico Sintase Tipo II , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-sis , Ratos , Ratos Wistar , Tioureia/farmacologiaRESUMO
This study was aimed at testing the hypothesis that the brain heme oxygenase (HO)-carbon monoxide (CO) pathway plays a role in stress fever. To this end, the effect of the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG), on restraint-induced fever was tested. Intracerebroventricular ZnDPBG (200 nmol) did not affect the body core temperature of unrestrained rats, but markedly attenuated restraint-induced fever. However, at the same dose, intraperitoneal ZnDPBG did not affect the febrile response to restraint. Taken together, these results indicate that the brain HO-CO pathway plays a major role in the genesis of stress fever in rats.
Assuntos
Encéfalo/enzimologia , Monóxido de Carbono/fisiologia , Febre/enzimologia , Heme Oxigenase (Desciclizante)/fisiologia , Estresse Fisiológico/enzimologia , Animais , Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
The elevated expression of stress proteins is considered to be a universal response to adverse conditions, representing a potential mechanism of cellular defense against disease and a potential target for novel therapeutics. Exposure to arsenicals either in vitro or in vivo in a variety of model systems has been shown to cause the induction of a number of the major stress protein families such as heat shock proteins (Hsp). Among them are members with low molecular weight, such as metallotionein and ubiquitin, as well as ones with masses of 27, 32, 60, 70, 90, and 110 kDa. In most of the cases, the induction of stress proteins depends on the capacity of the arsenical to reach the target, its valence, and the type of exposure, arsenite being the biggest inducer of most Hsp in several organs and systems. Hsp induction is a rapid dose-dependent response (1-8 h) to the acute exposure to arsenite. Thus, the stress response appears to be useful to monitor the sublethal toxicity resulting from a single exposure to arsenite. The present paper offers a critical review of the capacity of arsenicals to modulate the expression and/or accumulation of stress proteins. The physiological consequences of the arsenic-induced stress and its usefulness in monitoring effects resulting from arsenic exposure in humans and other organisms are discussed.
Assuntos
Arsênio/toxicidade , Proteínas de Choque Térmico/biossíntese , Animais , Arsênio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico HSP70/fisiologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/fisiologia , Heme Oxigenase (Desciclizante)/biossíntese , Heme Oxigenase (Desciclizante)/fisiologia , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Membrana/fisiologia , Metalotioneína/biossíntese , Metalotioneína/fisiologia , Estresse Oxidativo , Ubiquitina/biossínteseRESUMO
Free radical mediated oxidation of apoB lipoproteins in the arterial intima appears to contribute to atherogenicity of the entrapped particles. A plausible pathogenic mechanism for oxidation is the one induced by heme leaking from erythrocytes that is then carried into the arterial wall by its high affinity for lipoproteins. In the intima, in the presence of H(2)O(2) secreted by macrophages, heme can be a potent oxidant. To study the role of heme as a promoter of oxidative stress damage in vivo we used a model of intravascular hemolysis (IVH) caused by phenylhydrazine in rabbits with and without diet-induced moderate hypercholesterolemia (MHC). Evaluation of the antioxidant status of plasma indicated that at the end of the treatment period this was compromised by the MHC-IVH. After 10 weeks the animals with combined MHC-IVH showed more of the aorta surface covered by lesions (27%+/-8, mean (SD) than the animals with only MHC (11%+/-7), in spite of having similar plasma levels of VLDL+LDL lipoproteins. The animals with only IVH, as well as the controls, showed minimal lesions (<1%). Heme oxygenase (HO-1) expression in aorta and other tissues was markedly increased in the group with MHC-IVH and it was correlated with the extent of IVH. The data suggest that the oxidative stress associated with IVH potentiates the atherogenicity of moderate hypercholesterolemia and that in spite of a strong induction of HO-1 this is not sufficient to counteract the atherogenicity of the combined condition.
Assuntos
Arteriosclerose/fisiopatologia , Heme Oxigenase (Desciclizante)/genética , Hemólise/fisiologia , Hipercolesterolemia/complicações , Animais , Aorta/patologia , Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Dieta Aterogênica , Regulação da Expressão Gênica , Heme Oxigenase (Desciclizante)/fisiologia , Heme Oxigenase-1 , Hemoglobinas/análise , Hemólise/efeitos dos fármacos , Hipercolesterolemia/sangue , Masculino , Estresse Oxidativo , Fenil-Hidrazinas/farmacologia , CoelhosRESUMO
Carbon monoxide (CO) is a pollutant commonly recognized for its toxicological attributes, including CNS and cardiovascular effects. But CO is also formed endogenously in mammalian tissues. Endogenously formed CO normally arises from heme degradation in a reaction catalyzed by heme oxygenase. While inhibitors of endogenous CO production can raise arterial pressure, heme loading can enhance CO production and lead to vasodepression. Both central and peripheral tissues possess heme oxygenases and generate CO from heme, but the inability of heme substrate to cross the blood brain barrier suggests the CNS heme-heme oxygenase-CO system may be independent of the periphery. In the CNS, CO apparently acts in the nucleus tractus solitarii (NTS) promoting changes in glutamatergic neurotransmission and lowering blood pressure. At the periphery, the heme-heme oxygenase-CO system can affect cardiovascular functions in a two-fold manner; specifically: 1) heme-derived CO generated within vascular smooth muscle (VSM) can promote vasodilation, but 2) its actions on the endothelium apparently can promote vasoconstriction. Thus, it seems reasonable that the CNS-, VSM- and endothelial-dependent actions of the heme-heme oxygenase-CO system may all affect cardiac output and vascular resistance, and subsequently blood pressure.