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Sun HJ, Wang ZC, Nie XW, Bian JS. Therapeutic potential of carbon monoxide in hypertension-induced vascular smooth muscle cell damage revisited: from physiology and pharmacology. Biochem Pharmacol 2022; 199:115008. [PMID: 35318039 DOI: 10.1016/j.bcp.2022.115008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/13/2022] [Accepted: 03/15/2022] [Indexed: 01/14/2023]
Abstract
As a chronic and progressive disorder, hypertension remains to be a serious public health problem around the world. Among the different types of hypertension, pulmonary arterial hypertension (PAH) is a devastating disease associated with pulmonary arteriole remodeling, right ventricular failure and death. The contemporary management of systemic hypertension and PAH has substantially grown since more therapeutic targets and/or agents have been developed. Evolving treatment strategies targeting the vascular remodeling lead to improving outcomes in patients with hypertension, nevertheless, significant advancement opportunities for developing better antihypertensive drugs remain. Carbon monoxide (CO), an active endogenous gasotransmitter along with hydrogen sulfide (H2S) and nitric oxide (NO), is primarily generated by heme oxygenase (HO). Cumulative evidence suggests that CO is considered as an important signaling molecule under both physiological and pathological conditions. Studies have shown that CO confers a number of biological and pharmacological properties, especially its involvement in the pathological process and treatment of hypertension-related vascular remodeling. This review will critically outline the roles of CO in hypertension-associated vascular remodeling and discuss the underlying mechanisms for the protective effects of CO against hypertension and vascular remodeling. In addition, we will propose the challenges and perspectives of CO in hypertensive vascular remodeling. It is expected that a comprehensive understanding of CO in the vasculature might be essential to translate CO to be a novel pharmacological agent for hypertension-induced vascular remodeling.
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Affiliation(s)
- Hai-Jian Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Zi-Chao Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Xiao-Wei Nie
- Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518055, China.
| | - Jin-Song Bian
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215000, China.
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Arai Y, Ito M, Tanaka K, Ozawa J, Motojima Y, Matsuoka K, Igarashi K, Namba F. Increased expression of heme oxygenase-1 suppresses airway branching morphogenesis in fetal mouse lungs exposed to inflammation. Pediatr Res 2020; 87:494-500. [PMID: 31578032 DOI: 10.1038/s41390-019-0588-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 09/04/2019] [Accepted: 09/09/2019] [Indexed: 11/09/2022]
Abstract
BACKGROUND Intrauterine inflammation affects fetal lung development. BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1) and interleukin-6 (IL-6) genes. We investigated the role of Bach1 in the development of fetal mouse lungs exposed to lipopolysaccharide (LPS) using a whole fetal lung tissue culture system. METHODS We isolated and cultured embryonic day 12.5 fetal mouse lungs from pregnant Bach1 knockout (-/-) and wild-type (WT) mice. Airway branching morphogenesis was assessed by microscopically counting peripheral lung buds after incubation with/without LPS. Expression levels of genes related to inflammation and oxidative stress were evaluated using quantitative PCR. Zinc protoporphyrin, HO-1-specific inhibitor, was used. RESULTS Branching morphogenesis was observed in Bach1-/- and WT fetal mice lungs without LPS exposure; after exposure to LPS, the number of peripheral lung buds was suppressed in Bach1-/- group only. Basal messenger RNA (mRNA) and protein expression of HO-1 was significantly higher in Bach1-/- group than in WT group; IL-6 and monocyte chemoattractant protein-1 mRNA expression was significantly increased after LPS exposure in both groups. Zinc protoporphyrin mitigated the LPS-induced suppression of branching morphogenesis in Bach1-/- mice. CONCLUSION The ablation of Bach1 suppresses airway branching morphogenesis after LPS exposure by increased basal expression levels of HO-1.
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Affiliation(s)
- Yukio Arai
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, 350-8550, Japan
| | - Masato Ito
- Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Akita, 010-8543, Japan
| | - Kosuke Tanaka
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, 350-8550, Japan
| | - Junichi Ozawa
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, 350-8550, Japan
| | - Yukiko Motojima
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, 350-8550, Japan
| | - Kikumi Matsuoka
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, 350-8550, Japan
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Fumihiko Namba
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, 350-8550, Japan.
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Kilic-Toprak E, Kilic-Erkek O, Abban-Mete G, Caner V, Baris IC, Turhan G, Kucukatay V, Senol H, Kuru O, Bor-Kucukatay M. Contribution of Heme Oxygenase 2 to Blood Pressure Regulation in Response to Swimming Exercise and Detraining in Spontaneously Hypertensive Rats. Med Sci Monit 2018; 24:5851-5859. [PMID: 30132448 PMCID: PMC6116639 DOI: 10.12659/msm.908992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background We aimed to determine the effects of exercise followed by detraining on systolic blood pressure (SBP), heme oxygenase 2 (HO-2) expression, and carboxyhemoglobin (COHb) concentration in spontaneously hypertensive rats (SHR) to explain the role of carbon monoxide (CO) in this process. Material/Methods Animals were randomized into exercised and detrained groups. Corresponding sedentary rats were grouped as Time 1–2. Swimming of 60 min/5 days/week for 10 weeks was applied. Detraining rats discontinued training for an additional 5 weeks. Gene and protein expressions were determined by real-time PCR and immunohistochemistry. Results Aorta HO-2 histological scores (HSCORE) of hypertensive rats were lower, while SBP was higher. Swimming caused enhancement of HO-2 immunostaining in aorta endothelium and adventitia of SHR. Exercise induced elevation of blood COHb index in SHR. Synchronous BP lowering effect of exercise was observed. HO-2 mRNA expression, HSCORE, and blood COHb index were unaltered during detraining, while SBP was still low in SHR. Conclusions CO synthesized by HO-2 at least partly plays a role in SBP regulation in the SHR- and BP-lowering effect of exercise. Regular exercise with short-term pauses may be advised to both hypertensives and individuals who are at risk.
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Affiliation(s)
- Emine Kilic-Toprak
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Ozgen Kilic-Erkek
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Gulcin Abban-Mete
- Department of Histology-Embryology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Vildan Caner
- Department of Medical Genetics, Faculty of Medicine Kinikli, Pamukkale University, Denizli, Turkey
| | - Ikbal Cansu Baris
- Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Gurkan Turhan
- Department of Histology-Embryology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Vural Kucukatay
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Hande Senol
- Department of Biostatistics, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Oktay Kuru
- Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Melek Bor-Kucukatay
- Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
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Heme oxygenase-1 deficiency exacerbates angiotensin II-induced aortic aneurysm in mice. Oncotarget 2018; 7:67760-67776. [PMID: 27626316 PMCID: PMC5356517 DOI: 10.18632/oncotarget.11917] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 09/02/2016] [Indexed: 01/23/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) is a chronic but often fatal disease in elderly population. Heme oxygenase-1 (HO-1) is a stress response protein with antioxidative and anti-inflammatory properties. HO-1 has been shown to protect against atherogenesis and arterial intimal thickening. Emerging evidences suggest that AAA and arterial occlusive disease have distinct pathogenic mechanisms. Thus, in this study we investigated the role of HO-1 in angiotensin II-induced AAA formation in HO-1+/+apoE−/− and HO-1−/−apoE−/− mice. We found that complete loss of HO-1 increased AAA incidence and rupture rate, and drastically increased aneurysmal area and severity, accompanied with severe elastin degradation and medial degeneration. Interestingly, we often observed not only AAA but also thoracic aortic aneurysm in HO-1−/−apoE−/− mice. Furthermore, reactive oxygen species levels, vascular smooth muscle cell (VSMC) loss, macrophage infiltration, matrix metalloproteinase (MMP) activity were markedly enhanced in the aneurysmal aortic wall in HO-1−/−apoE−/− mice. In addition, HO-1−/−apoE−/− VSMCs were more susceptible to oxidant-induced cell death and macrophages from HO-1−/−apoE−/− mice had aggravated responses to angiotensin II with substantial increases in inflammatory cytokine productions and MMP9 activity. Taken together, our results demonstrate the essential roles of HO-1 in suppressing the pathogenesis of AAA. Targeting HO-1 might be a promising therapeutic strategy for AAA.
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Lee SR, Nilius B, Han J. Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation. Rev Physiol Biochem Pharmacol 2018; 174:81-156. [PMID: 29372329 DOI: 10.1007/112_2017_7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Carbon monoxide (CO), hydrogen sulfide (H2S), and nitric oxide (NO) constitute endogenous gaseous molecules produced by specific enzymes. These gases are chemically simple, but exert multiple effects and act through shared molecular targets to control both physiology and pathophysiology in the cardiovascular system (CVS). The gases act via direct and/or indirect interactions with each other in proteins such as heme-containing enzymes, the mitochondrial respiratory complex, and ion channels, among others. Studies of the major impacts of CO, H2S, and NO on the CVS have revealed their involvement in controlling blood pressure and in reducing cardiac reperfusion injuries, although their functional roles are not limited to these conditions. In this review, the basic aspects of CO, H2S, and NO, including their production and effects on enzymes, mitochondrial respiration and biogenesis, and ion channels are briefly addressed to provide insight into their biology with respect to the CVS. Finally, potential therapeutic applications of CO, H2S, and NO with the CVS are addressed, based on the use of exogenous donors and different types of delivery systems.
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Affiliation(s)
- Sung Ryul Lee
- Department of Convergence Biomedical Science, Cardiovascular and Metabolic Disease Center, College of Medicine, Inje University, Busan, Republic of Korea
| | - Bernd Nilius
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Jin Han
- National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Department of Health Sciences and Technology, BK21 Plus Project Team, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.
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Cardioprotective Effect of Selective Estrogen Receptor Modulator Raloxifene Are Mediated by Heme Oxygenase in Estrogen-Deficient Rat. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2176749. [PMID: 28770019 PMCID: PMC5523444 DOI: 10.1155/2017/2176749] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 05/17/2017] [Accepted: 05/25/2017] [Indexed: 01/26/2023]
Abstract
Estrogens and raloxifene (RAL) have beneficial effects on certain cardiovascular indices in postmenopausal women characterized by estrogen deficiency. Heme oxygenase (HO) activity is increased by 17β-estradiol (E2) and RAL in estrogen-deficient rat resulting in vasorelaxation mediated by carbon monoxide. We determined the expressions of HO in cardiac and aortic tissues after ovariectomy (OVX) and subsequent RAL or E2 treatment. We investigated the effects of pharmacological inhibition of HO enzyme on the arginine vasopressin- (AVP-) induced blood pressure in vivo, the epinephrine- and phentolamine-induced electrocardiogram ST segment changes in vivo, and the myeloperoxidase (MPO) enzyme activity. When compared with intact females, OVX decreased the HO-1 and HO-2 expression, aggravated the electrocardiogram signs of heart ischemia and the blood pressure response to AVP, and increased the cardiac MPO. E2 and RAL are largely protected against these negative impacts induced by OVX. The pharmacological inhibition of HO in E2- or RAL-treated OVX animals, however, restored the cardiovascular status close to that observed in nontreated OVX animals. The decreased expression of HO enzymes and the changes in blood pressure ischemia susceptibility and inflammatory state in OVX rat can be reverted by the administration of E2 or RAL partly through its antioxidant and anti-inflammatory roles.
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Detsika MG, Duann P, Lianos EA. HO-1 expression control in the rat glomerulus. Biochem Biophys Res Commun 2015; 460:786-92. [PMID: 25824035 DOI: 10.1016/j.bbrc.2015.03.107] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 03/20/2015] [Indexed: 11/30/2022]
Abstract
The differential localization of HO-1 in renal cells under conditions of injury, and the demonstration that exaggerated HO-1 expression can have detrimental rather than beneficial effects, raises the question of whether HO-1 expression in these cells is subject to control. The present study identifies a unique HO-1 expression pattern in the renal glomerulus indicative of presence of HO-1 expression control following prolonged HO-1 induction. HO-1 and HO-2 expression in response to the natural HO substrate/inducer Fe(++) protoporphyrin (PP) IX (hemin) was assessed in normal rat glomeruli. Following 18 h incubations with hemin (0-200 μM), HO-1 expression increased in a concentration-dependent manner and via a hemopexin (HPX) independent mechanism with no effect on HO-2. In incubations with higher hemin concentrations (400 μM), likely to be encountered in hemolytic disorders, HO-1 expression, decreased. This was preceded by a prolonged and sustained increase in HO-1 protein and was independent of the Fe(++) moiety as incubations with Cobalt protoporphyrin (CoPP) resulted in an identical expression pattern. The decrease of HO-1 protein could not be accounted for by proteasomal degradation since it was not reversed in co-incubations with hemin and the proteasome inhibitor, MG132, at concentrations sufficient to increase HO-1 glomerular content when used alone. Moreover, in the presence of MG132, a decrease of HO-1 expression also occurred at 100 and 200 μM hemin. The effect of MG132 was mimicked by two additional mechanistically different approaches which also raised HO-1 content: a) co-incubations of hemin with ZnPP which increased HO-1 protein when used alone, and b) glomerular HO-1 over expression achieved by SB transposon mediated transgenesis. In contrast, the decrease in HO-1 levels observed at high hemin concentrations was reversed in co-incubations with hemin and SnPP, which reduced HO-1 content when used alone. Expression of NF-E2 related factor 2 (Nrf2) protein, which mediates HO-1 induction in response to hemin, had a similar expression pattern with that of HO-1 protein indicating involvement of Nrf2 in the response of HO-1 to hemin. The above observations indicate presence of a HO-1 expression control mechanism in the glomerulus that may serve to protect it against potentially detrimental effects of exaggerated HO-1 expression.
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Affiliation(s)
- Maria G Detsika
- 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens School of Medicine, GP Livanos and M. Simou Laboratories, Athens, Greece.
| | - Pu Duann
- Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, New Brunswick, NJ, United States
| | - Elias A Lianos
- 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens School of Medicine, GP Livanos and M. Simou Laboratories, Athens, Greece; Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, New Brunswick, NJ, United States
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Therapeutic applications of carbon monoxide. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:360815. [PMID: 24648866 PMCID: PMC3932177 DOI: 10.1155/2013/360815] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/21/2013] [Accepted: 11/05/2013] [Indexed: 11/17/2022]
Abstract
Heme oxygenase-1 (HO-1) is a regulated enzyme induced in multiple stress states. Carbon monoxide (CO) is a product of HO catalysis of heme. In many circumstances, CO appears to functionally replace HO-1, and CO is known to have endogenous anti-inflammatory, anti-apoptotic, and antiproliferative effects. CO is well studied in anoxia-reoxygenation and ischemia-reperfusion models and has advanced to phase II trials for treatment of several clinical entities. In alternative injury models, laboratories have used sepsis, acute lung injury, and systemic inflammatory challenges to assess the ability of CO to rescue cells, organs, and organisms. Hopefully, the research supporting the protective effects of CO in animal models will translate into therapeutic benefits for patients. Preclinical studies of CO are now moving towards more complex damage models that reflect polymicrobial sepsis or two-step injuries, such as sepsis complicated by acute respiratory distress syndrome. Furthermore, co-treatment and post-treatment with CO are being explored in which the insult occurs before there is an opportunity to intervene therapeutically. The aim of this review is to discuss the potential therapeutic implications of CO with a focus on lung injury and sepsis-related models.
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Yu JB, Jianbo Y, Dong SA, Shuan D, Luo XQ, Xiaoqing L, Gong LR, Lirong G, Zhang Y, Yuan Z, Wang M, Man W, Cao XS, Xinshun C, Liu DQ, Daquan L. Role of HO-1 in protective effect of electro-acupuncture against endotoxin shock-induced acute lung injury in rabbits. Exp Biol Med (Maywood) 2013; 238:705-12. [PMID: 23918882 DOI: 10.1177/1535370213489487] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Heme oxygenase (HO)-1 has been reported to play a great role in attenuating lung injury during endotoxic shock in our previous research. Although electro-acupuncture has been explored to reduce oxidative stress and decrease inflammatory reaction in animals with endotoxic shock, the mechanism of this effect is still unclear. The aim of this study was to determine whether HO-1 is involved in the effect of electro-acupuncture on the injured lung during endotoxic shock in rabbits. Sixty New England white rabbits were randomly divided into groups C, Z, ES, EA, AP, and EAZ. Before inducing endotoxic shock, group ES received no electro-acupuncture, while group EA received electro-acupuncture at ST36 (zusanli) and BL13 (feishu) acupoints on both sides for five days and group AP received electro-acupuncture (EA) stimulation at a non-acupoint. Groups ES, AP, EA, and EAZ received LPS to replicate the experimental model of injured lung induced by endotoxic shock, and electro-acupuncture was performed throughout the procedure with the same parameter. Groups EAZ and Z received the HO-1 inhibitor, ZnPP-IX, intraperitoneally. The animals were sacrificed by blood-letting at 6 h after LPS administration. The blood samples were collected for serum examination, and the lungs were removed for pathology examination, detection of alveolaer epithelial cell apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL assay), determination of wet to dry ratio, measurement of Evans blue (EB) contents, and determination of HO-1protein and mRNA expression. According to the results, EA at ST36 and BL13 could increase the expression of HO-1. At the same time, index of quantitative assessment (IQA) score and the number of TUNEL-positive cells decreased, while electro-acupuncture at the other points did not exert this effect, and pretreatment with ZnPP-IX in group EAZ suppressed the efficacy of electro-acupuncture preconditioning. In summary, electro-acupuncture stimulation at ST36 and BL13, while not the non-acupoint, could attenuate the lung injury during the endotoxic shock, and this effect was due to increased expression of HO-1.
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Affiliation(s)
| | - Yu Jianbo
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, 300100, China.
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Antczak A, Ciebiada M, Kharitonov SA, Gorski P, Barnes PJ. Inflammatory markers: exhaled nitric oxide and carbon monoxide during the ovarian cycle. Inflammation 2012; 35:554-9. [PMID: 21590323 PMCID: PMC3314817 DOI: 10.1007/s10753-011-9345-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nitric oxide (NO) production and carbon monoxide (CO) production are increased in inflammatory lung diseases. Although there are some pieces of evidence for hormonal modulation by estrogen, little is known about exhaled NO and CO during the ovarian cycle. In 23 subjects, we measured exhaled NO and CO by an online analyzer. Significantly higher levels of exhaled NO were found at the midcycle compared with those in the premenstrual period or during menstruation. Higher levels of CO were after ovulation and reached a peak in the premenstrual phase. The lowest levels of CO were observed in the first days of the estrogen phase. In males, there was no significant variation in exhaled NO and CO. Exhaled NO and CO levels vary during the ovarian cycle in women, and this fact should be taken into account during serial measurements of these markers in the female population.
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Affiliation(s)
- Adam Antczak
- Department of Pneumology and Allergy, Medical University of Lodz, Kopcińskiego 22, 90-153 Łódź, Poland
| | - Maciej Ciebiada
- Department of Pneumology and Allergy, Medical University of Lodz, Kopcińskiego 22, 90-153 Łódź, Poland
| | - Sergei A. Kharitonov
- Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK
| | - Pawel Gorski
- Department of Pneumology and Allergy, Medical University of Lodz, Kopcińskiego 22, 90-153 Łódź, Poland
| | - Peter J. Barnes
- Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK
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Zhang Y, He LS, Zhang G, Xu Y, Lee OO, Matsumura K, Qian PY. The regulatory role of the NO/cGMP signal transduction cascade during larval attachment and metamorphosis of the barnacle Balanus (=Amphibalanus) amphitrite. ACTA ACUST UNITED AC 2012; 215:3813-22. [PMID: 22855617 DOI: 10.1242/jeb.070235] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The barnacle Balanus amphitrite is among the most dominant fouling species on intertidal rocky shores in tropical and subtropical areas and is thus a target organism in antifouling research. After being released from adults, the swimming nauplius undertakes six molting cycles and then transforms into a cyprid. Using paired antennules, a competent cyprid actively explores and selects a suitable substratum for attachment and metamorphosis (collectively known as settlement). This selection process involves the reception of exogenous signals and subsequent endogenous signal transduction. To investigate the involvement of nitric oxide (NO) and cyclic GMP (cGMP) during larval settlement of B. amphitrite, we examined the effects of an NO donor and an NO scavenger, two nitric oxide synthase (NOS) inhibitors and a soluble guanylyl cyclase (sGC) inhibitor on settling cyprids. We found that the NO donor sodium nitroprusside (SNP) inhibited larval settlement in a dose-dependent manner. In contrast, both the NO scavenger carboxy-PTIO and the NOS inhibitors aminoguanidine hemisulfate (AGH) and S-methylisothiourea sulfate (SMIS) significantly accelerated larval settlement. Suppression of the downstream guanylyl cyclase (GC) activity using a GC-selective inhibitor ODQ could also significantly accelerate larval settlement. Interestingly, the settlement inhibition effects of SNP could be attenuated by ODQ at all concentrations tested. In the developmental expression profiling of NOS and sGC, the lowest expression of both genes was detected in the cyprid stage, a crucial stage for the larval decision to attach and metamorphose. In summary, we concluded that NO regulates larval settlement via mediating downstream cGMP signaling.
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Affiliation(s)
- Yu Zhang
- KAUST Global Collaborative Research Program, Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
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Walther M, De Caul A, Aka P, Njie M, Amambua-Ngwa A, Walther B, Predazzi IM, Cunnington A, Deininger S, Takem EN, Ebonyi A, Weis S, Walton R, Rowland-Jones S, Sirugo G, Williams SM, Conway DJ. HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children. PLoS Pathog 2012; 8:e1002579. [PMID: 22438807 PMCID: PMC3305414 DOI: 10.1371/journal.ppat.1002579] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 01/26/2012] [Indexed: 01/16/2023] Open
Abstract
Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)(n) repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)(n) repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.
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Affiliation(s)
- Michael Walther
- Medical Research Council Laboratories, Fajara, Banjul, Gambia.
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Chen JH, Huang SM, Tan TW, Lin HY, Chen PY, Yeh WL, Chou SC, Tsai CF, Wei IH, Lu DY. Berberine induces heme oxygenase-1 up-regulation through phosphatidylinositol 3-kinase/AKT and NF-E2-related factor-2 signaling pathway in astrocytes. Int Immunopharmacol 2012; 12:94-100. [DOI: 10.1016/j.intimp.2011.10.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 10/20/2011] [Accepted: 10/27/2011] [Indexed: 01/13/2023]
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Chung SW, Kwon MY, Kang YH, Chung HT, Lee SJ, Kim HP, Perrella MA. Transforming growth factor-β1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2. J Cell Physiol 2011; 227:351-60. [PMID: 21437904 DOI: 10.1002/jcp.22741] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Heme oxygenase (HO)-1 is a cytoprotective molecule that is induced during the response to injury. An increase in HO-1 is an acute indicator of inflammation, and early induction of HO-1 has been suggested to correlate with severity of injury. While a great deal is known about the induction of HO-1 by inflammatory mediators and bacterial lipopolysaccharide (LPS), much less is known about the effects of anti-inflammatory mediators on HO-1 expression. Transforming growth factor (TGF)-β is known to play a critical role in suppressing the immune response, and the TGF-β1 isoform is expressed in inflammatory cells. Thus, we wanted to investigate whether TGF-β1 could inhibit the expression of HO-1 during exposure to an inflammatory stimulus in macrophages. Here we demonstrate that TGF-β1 is able to downregulate LPS-induced HO-1 in mouse macrophages, and this reduction in HO-1 occurred through signaling of TGF-β1 via its type I receptor, and activation of Smad2. This TGF-β1 response is dependent on an intact Ets-binding site (EBS) located 93 base pairs upstream from the mouse HO-1 transcription start site. This EBS is known to be important for Ets-2 transactivation of HO-1 by LPS stimulation, and we show that TGF-β1 is able to suppress LPS-induced Ets-2 mRNA and protein levels in macrophages. Moreover, silencing of Smad2 is able to prevent the suppression of both HO-1 and Ets-2 by TGF-β1 during exposure to LPS. These data suggest that the return of HO-1 to basal levels during the resolution of an inflammatory response may involve its downregulation by anti-inflammatory mediators.
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Affiliation(s)
- Su Wol Chung
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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Abstract
The reduction of neutrophil migration to an infectious focus is associated with a high mortality in severe sepsis. Previously, we showed that heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in sepsis induced by cecal ligation and puncture (CLP) model. We demonstrated that pretreatment, but not the combination of pretreatment plus posttreatment with zinc protoporphyrin IX (ZnPP IX), an HO inhibitor, prevented the reduction of CXCR2 on circulating neutrophils and the failure of intraperitoneal neutrophil migration to the site of infection. Consequently, bacterial dissemination, systemic inflammatory response, and organ injury were prevented. In addition, pretreatment with the HO inhibitor avoided hypotension and consequently increased survival. Moreover, in mice subjected to severe CLP, the pretreatment, but not the combination of pretreatment plus posttreatment with ZnPP IX, prevented the increase of plasmatic free heme observed in nontreated severe CLP. The administration of exogenous hemin to mice subjected to moderate sepsis consistently increased the mortality rate. Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with ZnPP IX enhances sepsis severity because of an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.
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Yu JB, Yao SL. Effect of heme oxygenase–endogenous carbon monoxide on mortality during septic shock in rats. Ir J Med Sci 2011; 178:491-6. [PMID: 19052841 PMCID: PMC2777231 DOI: 10.1007/s11845-008-0260-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Accepted: 10/31/2008] [Indexed: 12/31/2022]
Abstract
Aim To investigate the effect of HO–CO on mortality during septic shock in rats. Method Eighty rats were randomly divided into group-control, group ZnPP-IX, group SS, and group LZ. Results Death was significantly lower in group SS than in group LZ (P < 0.05). The MAP was significantly higher in the group LZ than in the group SS (P < 0.05). ALT, AST, Cr and BUN, MDA, and the lung EB contents, were significantly lower in the group SS than that in the group LZ (all P < 0.05). And CO and SOD activities were significantly higher in group SS than that in the group LZ (all P < 0.05). HO-1 mRNA, and HO-1 protein were significantly lower in the group LZ than in the group SS (P < 0.05), whereas HO-2 mRNA, and HO-2 protein were not significantly different among four groups (all P > 0.05). Conclusion The increased oxidative stress and end-organ damage is related to mortality during septic shock; while the hypotension partly contributing to HO-1 protein and CO has no obvious relation with it.
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Affiliation(s)
- J-b Yu
- Department of Anesthesiology, Tianjin Nankai Hospital, China.
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Varaksin AA, Puschina EV. Hydrogen Sulfide as a Regulator of Systemic Functions in Vertebrates. NEUROPHYSIOLOGY+ 2011. [DOI: 10.1007/s11062-011-9186-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Cerrito MG, Scagliarini A, Froio A, Liloia A, Busnelli M, Giovannoni R, Otterbein LE, Mainetti L, Villa M, Bach FH, Leone BE, Biasi GM, Lavitrano M. Heme Oxygenase-1 Inhibition Prevents Intimal Hyperplasia Enhancing Nitric Oxide-Dependent Apoptosis of Vascular Smooth Muscle Cells. Biol Pharm Bull 2011; 34:1204-14. [DOI: 10.1248/bpb.34.1204] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | | | - Alberto Froio
- Vascular Surgery Unit, Department of Surgical Sciences, University of Milano-Bicocca
| | - Angela Liloia
- Vascular Surgery Unit, Department of Surgical Sciences, University of Milano-Bicocca
| | - Marco Busnelli
- Molecular Medicine Laboratory, University of Milano-Bicocca
| | | | | | - Lara Mainetti
- Molecular Medicine Laboratory, University of Milano-Bicocca
| | - Matteo Villa
- Molecular Medicine Laboratory, University of Milano-Bicocca
| | - Fritz Heintz Bach
- Immunobiology Research Center, Department of Surgery, Harvard Medical School
| | | | - Giorgio Maria Biasi
- Vascular Surgery Unit, Department of Surgical Sciences, University of Milano-Bicocca
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Motawi TK, Darwish HA, Abd El Tawab AM. Effects of caffeic acid phenethyl ester on endotoxin-induced cardiac stress in rats: a possible mechanism of protection. J Biochem Mol Toxicol 2010; 25:84-94. [PMID: 21472898 DOI: 10.1002/jbt.20362] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 03/12/2010] [Accepted: 04/02/2010] [Indexed: 01/17/2023]
Abstract
Endotoxins (lipopolysaccharides; LPS) are known to cause multiple organ failure, including myocardial dysfunction. The present study aimed to investigate the mechanism of caffeic acid phenethyl ester (CAPE) protection against LPS-induced cardiac stress. Rats were allocated into three groups; group 1 served as a normal control group, group 2 (LPS) received a single intraperitoneal injection of LPS (10 mg/kg), group 3 (LPS + CAPE) was injected intraperitoneally with CAPE (10 mg/kg/day; solubilized in saline containing 20% tween 20) throughout a period of 10 days prior to LPS injection. Rats were maintained 4 h before sacrifice. Caffeic acid phenethyl ester pretreatment normalized LPS-enhanced activities of serum creatine kinase (CK) and lactate dehydrogenase (LDH) as well as glutathione peroxidase (GPx), and myeloperoxidase (MPO) in cardiac tissue. A significant reduction of the elevated levels of serum tumor necrosis factor-alpha (TNF-α) as well as serum and cardiac nitrite/nitrate (NOx) ) was achieved after CAPE pretreatment. CAPE also restored malondialdelyde (MDA), reduced glutathione (GSH), and cytosolic calcium (Ca2+ ) levels in the heart. A marked induction of cardiac heme oxygenase-1 (HO-1) protein level was detected in CAPE-pretreated group. Whereas, LPS-induced reduction of adenosine triphosphate (ATP) and phosphocreatine (PCr) levels was insignificantly changed. Conclusively, the early treatment with CAPE maintained antioxidant defences, reduced oxidative injury, cytokine damage, and inflammation but did not markedly improve energy status in cardiac tissue. The beneficial effect of CAPE might be mediated, at least in part, by the superinduction of HO-1.
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Affiliation(s)
- Tarek K Motawi
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo1 1562, Egypt
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20
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Yun N, Eum HA, Lee SM. Protective role of heme oxygenase-1 against liver damage caused by hepatic ischemia and reperfusion in rats. Antioxid Redox Signal 2010; 13:1503-12. [PMID: 20446775 DOI: 10.1089/ars.2009.2873] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This study investigated the time course of heme oxygenase (HO)-1 expression and the role of endogenous HO-1 in hepatic ischemia and reperfusion (I/R). Rats were pretreated with hemin, an HO-1 inducer, and zinc protoporphyrin (ZnPP), an HO-1 inhibitor. Hepatic HO activity increased at 1 h after reperfusion, reaching a maximum at 6 h after reperfusion and then declined. HO-1 mRNA and protein expression in I/R liver were upregulated prior to reperfusion and highly induced again by reperfusion. The ALT level was upregulated at all time points, with a peak at 4-6 h. This increase was augmented by ZnPP but attenuated by hemin. Lipid peroxidation and serum HMGB1 release significantly increased at 1 h after reperfusion and remained elevated throughout the 24 h of reperfusion period, whereas the glutathione content decreased markedly at 4-6 h after reperfusion. These changes were attenuated by hemin but augmented by ZnPP. The levels of serum TNF-α, iNOS, and COX-2 protein and mRNA expressions were upregulated after reperfusion, further enhanced by ZnPP, and suppressed by hemin. HO-1 overexpression protects the liver against I/R injury by modulating oxidative stress and proinflammatory mediators.
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Affiliation(s)
- Nari Yun
- School of Pharmacy, Sungkyunkwan University , Suwon-si, South Korea
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21
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Jones AW, Durante W, Korthuis RJ. Heme oxygenase-1 deficiency leads to alteration of soluble guanylate cyclase redox regulation. J Pharmacol Exp Ther 2010; 335:85-91. [PMID: 20605906 PMCID: PMC2957777 DOI: 10.1124/jpet.110.169755] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Accepted: 07/02/2010] [Indexed: 01/19/2023] Open
Abstract
Heme oxygenase-1 knockout, H(mox)1(-/-), mice exhibit exacerbated vascular lesions after ischemia-reperfusion and mechanical injury. Surprisingly, we found no studies that reported contractile responses and sensitivity to vasorelaxants in H(mox)1(-/-) mice. The contractile responses [superior mesenteric arteries (SMA), from female H(mox)1(-/-) mice] exhibited increased sensitivity to phenylephrine (p < 0.001). Cumulative addition of acetylcholine relaxed SMA, with the residual contraction remaining 2 times higher in H(mox)1(-/-) mice (p < 0.001). Sodium nitroprusside (SNP, an NO donor) and 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole [YC-1; acts directly on soluble guanylate cyclase (sGC)] led to further relaxation, yet the residual contraction remained 2 to 3 times higher in H(mox)1(-/-) than H(mox)1(+/+) mice (p < 0.001). Branches from H(mox)1(-/-) mesenteric and renal arteries also showed reduced relaxation (p < 0.025). Relaxation of SMA was measured to 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4'-(trifluoromethyl) biphenyl-4-yl] methoxy}phenyl)ethyl]amino}benzoic acid (BAY 60-2770), which is a more effective activator of oxidized/heme-free sGC; and to 5-cyclopropyl-2-{1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl}-pyrimidin-4-ylamine (BAY 41-2272), a more effective stimulator of reduced sGC. H(mox)1(-/-) arteries were 15 times more sensitive to BAY 60-2770 (p < 0.025) than were H(mox)1(+/+) arteries. Pretreatment with 1H-[1,2,4]oxadiazolo[3,4-a]quinoxalin-1-one (ODQ), an oxidizer of sGC, predictably shifted the BAY 60-2770 response of H(mox)1(+/+) to the left (p < 0.01) and BAY 41-2272 response to the right (p < 0.01). ODQ had little effect on the responses of H(mox)1(-/-) arteries, indicating that much of sGC was oxidized/heme-free. Western analyses of sGC in SMA indicated that both α1 and β1 subunit levels were reduced to <50% of H(mox)1(+/+) level (p < 0.025). These findings support the hypothesis that the antioxidant function of H(mox)1 plays a significant role in the maintenance of sGC in a reduced state, which is resistant to degradation and is sensitive to NO. This function may be especially important in reducing vascular damage during ischemia-reperfusion injury.
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Affiliation(s)
- Allan W Jones
- Department of Medical Pharmacology, and Physiology, University of Missouri-Columbia, Columbia, MO 65212, USA.
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22
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Stec DE, Vera T, Storm MV, McLemore GR, Ryan MJ. Blood pressure and renal blow flow responses in heme oxygenase-2 knockout mice. Am J Physiol Regul Integr Comp Physiol 2009; 297:R1822-8. [PMID: 19846746 DOI: 10.1152/ajpregu.00319.2009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Heme oxygenase (HO) is the enzyme responsible for the breakdown of heme-generating carbon monoxide (CO) and biliverdin in this process. HO-2 is the constitutively expressed isoform in most tissues, such as the kidney and vasculature. CO generated by HO is believed to be an important vasodilator in the renal circulation along with another gas, nitric oxide (NO). To determine the importance of HO-2 in the regulation of blood pressure and renal blood flow (RBF), we treated HO-2 knockout (KO) mice chronically with either ANG II or N(G)-nitroarginine methyl ester (l-NAME). Basal blood pressures were not different between wild-type (WT), heterozygous (HET), or KO mice and averaged 113 +/- 3 vs. 115 +/- 2 vs. 116 +/- 2 mmHg. Similar increases in blood pressure to chronic ANG II as well as l-NAME treatment were observed in all groups with blood pressures increasing an average of 30 mmHg in response to ANG II and 15 mmHg in response to l-NAME. Basal RBFs were not different between the groups averaging 6.0 +/- 0.5 (n = 6) vs. 4.8 +/- 0.6 (n = 10) vs. 5.8 +/- 0.7 (n = 6) ml*min(-1)*g(-1) kidney weight in WT, HET, and KO mice. HO-2 KO and HET mice exhibited an attenuated decrease in RBF in response to acute administration of ANG II, while no differences were observed with l-NAME. Our data indicate that blood pressure and RBF responses to increased ANG II or inhibition of nitric oxide are not significantly enhanced in HO-2 KO mice.
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Affiliation(s)
- David E Stec
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39215, USA.
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Samora JB, Goodwill AG, Frisbee JC, Boegehold MA. Growth-dependent changes in the contribution of carbon monoxide to arteriolar function. J Vasc Res 2009; 47:23-34. [PMID: 19672105 DOI: 10.1159/000231718] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2008] [Accepted: 12/31/2008] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Endothelium-dependent dilation of skeletal muscle arterioles is mediated by unknown factors in very young rats. We assessed the possible contribution of carbon monoxide (CO) to this dilation and to dilation in older animals. METHODS The effects of de-endothelialization or various pharmacological inhibitors on responses to CO or endothelium-dependent dilators were studied in gracilis muscle arterioles from rats at 3-4 weeks ('weanlings') and 6-7 weeks ('juveniles'). RESULTS Exogenous CO constricted, rather than dilated, arterioles from both age groups. This constriction was reduced by endothelial removal or NOS inhibition in juvenile, but not weanling, arterioles. In contrast, this constriction was abolished by K(+) channel inhibition in weanling, but not juvenile, arterioles. The heme precursor delta-aminolevulinic acid constricted juvenile arterioles but did not affect weanling arterioles. The heme oxygenase inhibitor chromium (III) mesoporphyrin IX abolished the endothelium-dependent dilation of juvenile arterioles to simvastatin, and reduced ACh- and simvastatin-induced dilations of weanling arterioles. CONCLUSION These findings suggest that relatively high concentrations of exogenous CO can cause constriction by inhibiting endothelium-derived NO in juvenile arterioles and inhibiting K(+) channels in weanling arterioles. Endogenous CO produced at lower concentrations can contribute to endothelium-dependent dilation in both age groups.
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Affiliation(s)
- Julie Balch Samora
- Department of Physiology and Pharmacology, and Center for Interdisciplinary Research in Cardiovascular Sciences, West Virginia University School of Medicine, Morgantown, W. Va., USA
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Park YY. Ischemia/reperfusion Lung Injury Increases Serum Ferritin and Heme Oxygenase-1 in Rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2009; 13:181-7. [PMID: 19885035 DOI: 10.4196/kjpp.2009.13.3.181] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2009] [Revised: 05/11/2009] [Accepted: 05/25/2009] [Indexed: 01/11/2023]
Abstract
Intestinal ischemia/reperfusion (I/R) is one of common causes of acute lung injury (ALI). Early and accurate diagnosis of patients who are like to develop serious acute respiratory distress syndrome (ARDS) would give a therapeutic advantage. Ferritin and heme oxygenase-1 (HO-1) are increased by oxidative stress and are potential candidates as a predictive biomarker of ARDS. However, the mechanisms responsible for the increases of ferritin and HO-1, and their relationship to ALI, are unclear. In order to elucidate the interactions between ferritin and HO-1, we studied the changes in ferritin and HO-1 levels in serum and bronchoalveolar lavage (BAL) fluid after intestinal I/R injury in rats. Leukocyte number and protein contents in BAL fluid were elevated following I/R, and the increases were attenuated by mepacrine pretreatment. Both serum ferritin and HO-1 concentrations were progressively elevated throughout the 3 h observation period. Mepacrine pretreatment attenuated the increase of serum and BAL fluid ferritin concentrations, but did not suppress the increase of serum HO-1. Moreover, BAL fluid HO-1 levels did not change after I/R or after mepacrine pretreated I/R compared with sham rats. Unlike ferritin, HO-1 levels are not exactly matched with the ALI. Therefore, there might be a different mechanism between the changes of ferritin and HO-1 in intestinal I/R-induced ALI model.
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Affiliation(s)
- Yoon-Yub Park
- Department of Physiology, School of Medicine, Catholic University of Daegu, Daegu 705-718, Korea
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Yu JB, Zhou F, Yao SL, Tang ZH, Wang M, Chen HR. Effect of heme oxygenase-1 on the kidney during septic shock in rats. Transl Res 2009; 153:283-7. [PMID: 19446282 DOI: 10.1016/j.trsl.2009.01.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2008] [Revised: 01/06/2009] [Accepted: 01/07/2009] [Indexed: 10/21/2022]
Abstract
The aim of this study was to clarify the effect of heme oxygenase (HO)-1 on the kidney during septic shock in rats. Eighty healthy and clean Sprague-Dawley rats were randomly divided into 4 groups: control group (group C) , septic shock group (group SS) , lipopolysaccharide plus ZnPP-IX group (group LZ) , and ZnPP-IX (group Z) . The plasma levels of COHb, Cr, and BUN; the urine levels of gamma-GTP, alpha1-MG, RBP, and NAG; and MDA content, SOD activity; HO-1mRNA; HO-2mRNA; HO-1 protein; and HO-2 protein from kidney were measured. The plasma levels of Cr and BUN; the urine levels of gamma-GTP, alpha1-MG, RBP, and NAG; and MDA content from kidney in group SS were obviously higher than in group C and Z (both P < 0.05), respectively, but lower than in group LZ (both P < 0.05), respectively. In contrast, the plasma levels of COHb and SOD activity from kidney in group SS were obviously lower than those in group C and Z (both P < 0.05), respectively, but higher than in group LZ (both P < 0.05), respectively. The HO-1mRNA and HO-1 protein of nephridial tissue in group LZ were obviously higher than in group C and Z, respectively (both P < 0.05), but lower than in group SS, respectively (both P < 0.05). There were no significant differences of HO-2mRNA and HO-2 protein among these 4 groups (both P > 0.05). It is concluded that upregulation of the HO-1 protein might contribute to the protection of kidney during septic shock in rats.
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Affiliation(s)
- Jian-Bo Yu
- Department of Anesthesiology, Tianjin Medical University, Tianjin, China.
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Heeba G, Moselhy ME, Hassan M, Khalifa M, Gryglewski R, Malinski T. Anti-atherogenic effect of statins: role of nitric oxide, peroxynitrite and haem oxygenase-1. Br J Pharmacol 2009; 156:1256-66. [PMID: 19226281 DOI: 10.1111/j.1476-5381.2009.00125.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE The pleiotropic effects of HMG-CoA inhibitors (statins), which include anti-inflammation, antioxidation and immunomodulation, are not yet fully understood. The present study was designed to elucidate the role of nitric oxide (NO), peroxynitrite (ONOO(-)) and haem oxygenase-1 (HO-1) in the anti-atherogenic effect of statins. EXPERIMENTAL APPROACH Normal and atherosclerotic New Zealand rabbits were treated with atorvastatin or simvastatin in the presence or absence of inhibitors and promoters of endothelial nitric oxide synthase (eNOS) and HO-1. NO and ONOO(-) released from isolated aortae by calcium ionophore were measured with nanosensors placed 6 +/- 2 nm from aortic endothelium. Expression of eNOS and HO-1 protein, HO activity, plasma malondialdehyde (MDA) and vessel wall thickness were also measured. KEY RESULTS Hypercholesterolaemia decreased eNOS expression by 31 +/- 3%, decreased NO (230 +/- 16 vs. 433 +/- 17 nmol x L(-1) control) and increased cytotoxic ONOO(-) (299 +/- 15 vs. 187 +/- 11 nmol x L(-1) control). The concentration ratio of [NO]/[ONOO(-)] decreased from 2.3 +/- 0.1 (normal) to 0.7 +/- 0.1 indicating an increase of nitroxidative stress in atherosclerotic endothelium. Expression of HO-1 protein increased by 20 +/- 8% in atherosclerosis and further increased (about 30%) after treatment with statins. Statins partially restored the [NO]/[ONOO(-)] balance (1.5 +/- 0.1 for atorvastatin and 1.4 +/- 0.1 simvastatin), decreased MDA and wall thickening. Promoters of eNOS and HO-1 (L-arginine and haemin) ameliorated the [NO]/[ONOO(-)] ratio while their inhibitors (L-NAME or tin-protoporphyrin) showed no improvement in these ratio. CONCLUSIONS AND IMPLICATIONS Atherosclerosis induced an endothelial [NO]/[ONOO(-)] balance indicative of endothelial dysfunction. Statins showed anti-atherosclerotic effects mediated by HO-1/eNOS, restoring the [NO]/[ONOO(-)] imbalance and reducing lipid peroxidation.
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Affiliation(s)
- G Heeba
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701-2979, USA
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NS398 protects cells from sodium nitroprusside-mediated cytotoxicity through enhancing HO-1 induction independent of COX-2 inhibition. Arch Pharm Res 2009; 32:99-107. [DOI: 10.1007/s12272-009-1123-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Revised: 11/26/2008] [Accepted: 12/02/2008] [Indexed: 01/16/2023]
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Furuichi M, Yokozuka M, Takemori K, Yamanashi Y, Sakamoto A. The reciprocal relationship between heme oxygenase and nitric oxide synthase in the organs of lipopolysaccharide-treated rodents. Biomed Res 2009; 30:235-43. [DOI: 10.2220/biomedres.30.235] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Kinobe RT, Dercho RA, Nakatsu K. Inhibitors of the heme oxygenase - carbon monoxide system: on the doorstep of the clinic? Can J Physiol Pharmacol 2008; 86:577-99. [PMID: 18758507 DOI: 10.1139/y08-066] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This 'next generation' of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO.
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Affiliation(s)
- Robert T Kinobe
- Department of Pharmacology and Toxicology, Queen's University, Kingston, ON Canada
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Chang T, Wu L, Wang R. Inhibition of vascular smooth muscle cell proliferation by chronic hemin treatment. Am J Physiol Heart Circ Physiol 2008; 295:H999-H1007. [PMID: 18621849 DOI: 10.1152/ajpheart.01289.2007] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Hemin, an oxidized form of heme, is an essential regulator of gene expression and cell cycle progression. Our laboratory previously reported (34) that chronic hemin treatment of spontaneously hypertensive rats reversed the eutrophic inward remodeling of small peripheral arteries. Whether long-term treatment of cultured vascular smooth muscle cells (VSMCs) with hemin alters the proliferation status of these cells has been unknown. In the present study, hemin treatment at 5 muM for 4, 7, 14, and 21 days significantly inhibited the proliferation of cultured rat aortic VSMCs (A-10 cells) by arresting cells at G0/G1 phases so as to decelerate cell cycle progression. Heme oxygenase (HO) activity and inducible HO-1 protein expression were significantly increased by hemin treatment. HO inhibitor tin protoporphyrin IX (SnPP) abolished the effects of hemin on cell proliferation and HO activity. Interestingly, hemin-induced HO-1 expression was further increased in the presence of SnPP. Hemin treatment had no significant effect on the expression of constitutive HO-2. Expression of p21 protein and the level of reactive oxygen species (ROS) were decreased by hemin treatment, which was reversed by application of SnPP. After removal of hemin from culture medium, inhibited cell proliferation and increased HO-1 expression in VSMCs were returned to control level within 1 wk. Transfection with HO-1 small interfering RNA significantly knocked down HO-1 expression and decreased HO activity, but had no effect on HO-2 expression, in cells treated with or without hemin for 7 days. The inhibitory effect of hemin on cell proliferation was abolished in HO-1 silenced cells. It is concluded that induction of HO-1 and, consequently, increased HO activity are responsible for the chronic inhibitory effect of hemin on VSMC proliferation. Changes in the levels of p21 and ROS might also participate in the cellular effects of hemin.
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Affiliation(s)
- Tuanjie Chang
- Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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31
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Jin YC, Gam SC, Jung JH, Hyun JS, Chang KC, Hyun JS. Expression and activity of heme oxygenase-1 in artificially induced low-flow priapism in rat penile tissues. J Sex Med 2008; 5:1876-82. [PMID: 18554260 DOI: 10.1111/j.1743-6109.2008.00886.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
INTRODUCTION The inducible isoform of heme oxygenase (HO)-1 regulates the vascular smooth muscle tone and responds to hypoxia. AIM To investigate the role of HO-1 in a low-flow priapism. MATERIALS AND METHODS Sixty male Sprague-Dawley rats were divided into five groups of six rats each. Each group of rats was sacrificed at 0 hour (group 1, control), 4 hours (group 2), 8 hours (group 3), 12 hours (group 4), and 24 hours (group 5) after inducing an artificial veno-occlusive priapism. The changes of the expression and activity of HO-1, and the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and levels of cyclic guanosine monophosphate in the penis were examined in a low-flow priapism. In addition, the HO-1 expression level in the aortas from each group was simultaneously measured to determine whether the changes in HO-1 were systemic. MAIN OUTCOME MEASURES The expression and activity of HO-1 was examined in artificially induced veno-occlusive priapism in rat penile tissues. RESULTS The expression of the HO-1 protein and the HO-1 enzyme activities in the penile tissues were gradually increased as time increased from 0 to 24 hours (P < 0.01). HO-1 immunoreactivities were localized in the endothelial layer of the cavernosal sinusoids. The expression of iNOS were also increased at 12 and 24 hours. The cyclic guanosine monophosphate level was also significantly increased at 24 hours (P < 0.05). However, the expression of the eNOS protein showed no statistically significant change with time, and the expression of the HO-1 protein in the aorta also showed no significant change with time. CONCLUSIONS A higher induction of HO-1 with time was observed in artificially induced veno-occlusive priapism, which might play a protective role against hypoxic injury. However, this may also play an important role in the vicious circle observed in a low-flow priapism.
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Affiliation(s)
- Yong Chun Jin
- Department of Pharmacology, School of Medicine, Gyeongsang National University Hospital, 90 Chilamdong, Jinju 660-702, South Korea
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32
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Bartolome S, Wood JG, Casillan AJ, Simpson SQ, O'Brien-Ladner AR. Activated protein C attenuates microvascular injury during systemic hypoxia. Shock 2008; 29:384-7. [PMID: 17693940 DOI: 10.1097/shk.0b013e31814544c2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In response to hypoxia, an inflammatory cascade is initiated and microvascular injury ensues. Specifically, within 10 min, leukocyte adherence to the endothelium begins, and leukocyte emigration and vascular leak soon follow. Activated protein C (APC) has been reported to have both anticoagulant and anti-inflammatory properties. Activated protein C is best described in its role as a treatment for sepsis. However, it has been used, with some success, in experimental models of hypoxic injury. We hypothesized that APC would be protective against microvascular injury during systemic hypoxia. Randomized prospective animal study. Adult male Sprague-Dawley rats. To characterize the microvascular response to APC exposure during hypoxia, four rat groups were used: saline control, APC infusion alone (100 mg/kg bolus), hypoxia alone (10% O2), and simultaneous hypoxia + APC infusion. Measurements of leukocyte adherence (no. per 100-microm venule), leukocyte emigration (no. per 4,000 microm(2)), and venular leak by fluorescein isothiacyanate-labeled albumin (Fo/Fi) were performed during intravital microscopy of the intact venular bed. Leukocyte adherence decreased from 14.5 (+/-1.2) cells/100-microm venule in hypoxic rats to 4.4 (+/-1.5) cells/100-microm venule in those treated with both hypoxic gas and APC infusion (P < 0.001). Similarly, leukocyte emigration in hypoxic rats reached 12.3 (+/- 2.2) cells/4,000-microm(2) venule, but was reduced to 3.5 (+/-0.3) cells/4,000-microm(2) venule (P <.001). Venular permeability to protein was also significantly decreased in the APC-treated group from 0.82 (+/-0.14) to 0.25 (+/-0.14) (P < 0.001). The infusion of APC attenuates the inflammatory response during systemic hypoxia at the microvascular level, as evidenced by measurements of leukocyte adherence, emigration, and venular permeability. Further investigation is needed to examine the potential role of APC in the treatment of hypoxic injury.
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Affiliation(s)
- Sonja Bartolome
- Department of Pulmonary Critical Care Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
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33
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Vareille M, Rannou F, Thélier N, Glasser AL, de Sablet T, Martin C, Gobert AP. Heme Oxygenase-1 Is a Critical Regulator of Nitric Oxide Production in EnterohemorrhagicEscherichia coli-Infected Human Enterocytes. THE JOURNAL OF IMMUNOLOGY 2008; 180:5720-6. [DOI: 10.4049/jimmunol.180.8.5720] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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34
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Sun JJ, Kim HJ, Seo HG, Lee JH, Yun-Choi HS, Chang KC. YS 49, 1-(alpha-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, regulates angiotensin II-stimulated ROS production, JNK phosphorylation and vascular smooth muscle cell proliferation via the induction of heme oxygenase-1. Life Sci 2007; 82:600-7. [PMID: 18262205 DOI: 10.1016/j.lfs.2007.12.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 11/30/2007] [Accepted: 12/08/2007] [Indexed: 02/07/2023]
Abstract
Overexpression of the gene for heme oxygenase (HO)-1 leads to a reduction in pressor responsiveness to angiotensin II (Ang II) in experimental animals. Using rat vascular smooth muscle cells (VSMCs), we tested whether YS 49 [1-(alpha-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits Ang II-stimulated proliferation of VSMCs via induction of HO-1. YS 49 induced HO-1 protein production in a dose-and time-dependent manner in VSMCs. Treatment with YS 49 significantly and dose-dependently inhibited Ang II-induced VSMC proliferation, ROS production, and phosphorylation of JNK, but not P38 MAP kinase or ERK1/2. The antiproliferation effect of YS 49 was reversed by pretreatment with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), or with hemoglobin, a carbon monoxide (CO) scavenger. Similarly, VSMC proliferation, ROS production and phosphorylation of JNK by Ang II were significantly inhibited in VSMCs transfected with the HO-1 gene. Thus, HO-1 and the HO-1 product CO play, at least in part, a crucial role in Ang II-stimulated VSMC proliferation through the regulation of ROS production and JNK phosphorylation. Therefore, YS 49 has potential as a therapeutic strategy for the pathogenesis of Ang II-related vascular diseases such as hypertension and atherosclerosis, via the induction of HO-1 gene activity.
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Affiliation(s)
- Jin Ji Sun
- Department of Pharmacology, School of Medicine, Gyeongsang National University 92 Chilam-dong, Jinju, South Korea
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35
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Abstract
Heme oxygenase-1 (HO-1) is a cytoprotective protein whose expression is consistently associated with therapeutic benefits in a number of pathologic conditions such as atherosclerotic vascular disease and inflammation. Although the expression of HO-1 in most tissues is low, a large number of clinical and experimental pharmacologic compounds have been demonstrated to induce HO-1. This induction is suggested to be at least partially responsible for the perceived therapeutic efficacy of these compounds. The increase in HO-1 expression in response to these compounds is the result of a complex regulatory network involving many signaling pathways and transcription factors. Understanding both the pathways by which HO-1 is induced and the mechanism through which the enzyme exerts its beneficial effects may facilitate the development of novel drugs.
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Affiliation(s)
- Cheng Li
- Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Australia
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36
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Alexander PG, Chau L, Tuan RS. Role of nitric oxide in chick embryonic organogenesis and dysmorphogenesis. ACTA ACUST UNITED AC 2007; 79:581-94. [PMID: 17676596 DOI: 10.1002/bdra.20386] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Nitric oxide (NO), produced by the nitric oxide synthase family of enzymes, mediates multiple signaling functions, and when unchecked, NO causes pathological damage. Exposure of embryos to a variety of teratogens, including carbon monoxide (CO), has been shown to increase reactive intermediates, such as NO, and recent work showed that either the excess or absence of NO caused morphological defects. While endogenous NO is known to regulate many adult tissues, its role during embryonic organogenesis and/or in mediating responses to teratogen exposure has not been explored. METHODS We have examined here the presence of NO during normal chick embryonic organogenesis, and investigated the teratogenicity of NO through the application of sodium nitroprusside (SNP), which mimics NO overproduction, and NG-monomethyl-L-arginine (L-NMMA), which inhibits endogenous NOS activity. RESULTS Topical treatment with SNP or L-NMMA for 18 h resulted in morphological defects, specifically in the neural tube and somites, which corresponded to sites of altered apoptosis. The location of NO was histochemically correlated with the observed morphological defects. Coadministration of SNP or L-NMMA with CO showed functional coregulation and interaction between NO and CO in chick embryonic development. CONCLUSIONS Our results showed that regulation of NO is essential for normal axial development, that sites of altered NO expression correlate to those of altered apoptosis and dysmorphogenesis, and that CO coadministration resulted in a rectification of normal NO expression. Collectively, these results suggest that alteration in endogenous NO/CO signaling is responsible, at least in part, for the observed NO-induced teratogenesis.
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Affiliation(s)
- Peter G Alexander
- Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-8022, USA
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37
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Froh M, Conzelmann L, Walbrun P, Netter S, Wiest R, Wheeler MD, Lehnert M, Uesugi T, Scholmerich J, Thurman RG. Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. World J Gastroenterol 2007; 13:3478-86. [PMID: 17659695 PMCID: PMC4146784 DOI: 10.3748/wjg.v13.i25.3478] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of heme oxygenase-1 (HO-1) against oxidant-induced injury caused by bile duct ligation (BDL).
METHODS: Either cobalt protoporphyrin (CoPP), a HO-1 inducer, or saline were injected intraperitoneally in male SD-rats. Three days later, BDL or sham-operations were performed. Rats were sacrificed 3 wk after BDL and livers were harvested for histology. Fibrosis was evaluated by sirius red staining and image analysis. Alpha-smooth muscular actin, which indicates activation of stellate cells, was detected by immunohistochemical staining, and cytokine and collagen-Iα (Col-Iα) mRNA expression was detected using RNase protection assays.
RESULTS: Serum alanine transaminase increased 8-fold above normal levels one day after BDL. Surprisingly, enzyme release was not reduced in rats receiving CoPP. Liver fibrosis was evaluated 3 wk after BDL and the sirius red-positive area was found to be increased to about 7.8%. However, in CoPP pretreated rats sirius red-positive areas were increased to about 11.7% after BDL. Collagen-Iα and TGF-β mRNA increased significantly by BDL. Again, this effect was increased by HO-1 overexpression.
CONCLUSION: Hepatic fibrosis due to BDL is not reduced by the HO-1 inducer CoPP. In contrast, HO-1 overexpression increases liver injury in rats under conditions of experimental chronic cholestasis.
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Affiliation(s)
- Matthias Froh
- Department of Internal Medicine, University of Regensburg, Regensburg 93042, Germany.
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38
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Goldberg A, Parolini M, Chin BY, Czismadia E, Otterbein LE, Bach FH, Wang H. Toll‐like receptor 4 suppression leads to islet allograft survival. FASEB J 2007; 21:2840-8. [PMID: 17475921 DOI: 10.1096/fj.06-7910com] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Carbon monoxide (CO) exposure of an islet donor frequently leads to islet allograft long-term survival and tolerance in recipients. We show here that CO confers its protective effects at least in part by suppressing Toll-like receptor 4 (TLR4) up-regulation in pancreatic beta cells. TLR4 is normally up-regulated in islets during the isolation procedure; donor treatment with CO suppresses TLR4 expression in isolated islets as well as in transplanted grafts. TLR4 up-regulation allows initiation of inflammation, which leads to islet allograft rejection; islet grafts from TLR4-deficient mice survive indefinitely in BALB/c recipients and show significantly less inflammation at various days after transplantation compared with grafts from a control donor. Isolated islets preinfected with a TLR4 dominant negative virus before transplantation demonstrated prolonged survival in recipients. Despite the salutary effects of TLR4 suppression, HO-1 expression is still needed in the recipient for islet survival: TLR4-deficient islets were rejected promptly after being transplanted into recipients in which HO-1 activity was blocked. In addition, incubation of an insulinoma cell line, betaTC3, with an anti-TLR4 antibody protects those cells from cytokine-induced apoptosis. Our data suggest that TLR4 induction in beta cells is involved in beta cell death and graft rejection after transplantation. CO exposure protects islets from rejection by blocking TLR4 up-regulation.
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Affiliation(s)
- Alyssa Goldberg
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215, USA
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39
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Eipel C, Eisold M, Schuett H, Vollmar B. Inhibition of Heme Oxygenase-1 Protects Against Tissue Injury in Carbon Tetrachloride Exposed Livers. J Surg Res 2007; 139:113-20. [PMID: 17275847 DOI: 10.1016/j.jss.2006.09.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Revised: 08/29/2006] [Accepted: 09/08/2006] [Indexed: 01/22/2023]
Abstract
BACKGROUND/AIMS During the metabolism of the hepatotoxin carbon tetrachloride (CCl(4)) by cytochrome P450, heme, and free radicals are released. Heme oxygenase (HO-1) is an enzyme that is induced by heme as well as oxidative stress and has been reported to be involved in mediating protection against toxic liver injury. The purpose of the present study was to specify the role of HO-1 in CCl(4)-hepatotoxicity. METHODS AND RESULTS We could demonstrate an up-regulation of HO-1 protein in CCl(4)-exposed liver tissue that reaches its maximum after 6 to 12 h, along with intrahepatic leukocyte accumulation and tissue injury. When animals were pretreated with hemin for augmentation of HO-1 expression, CCl(4)-exposure was associated with a reduction of intrahepatic leukocyte accumulation, while inhibition of CCl(4)-induced HO-1 expression by tin protoporphyrin-IX (SnPP-IX) enhanced leukocytic response. Of interest, however, liver morphology, transaminases, and bile flow as parameters of hepatocellular integrity and excretory function did not concur with reduced leukocyte numbers in the hepatic microcirculation, and revealed best organ function and tissue preservation in case of HO-1 inhibition by SnPP-IX. In contrast, hemin-treated CCl(4)-exposed livers demonstrated pathologic enzyme release and cholestasis. CONCLUSIONS Taken together, inhibition of HO-1 in CCl(4)-hepatotoxicity protected the liver, while higher HO-1 activity harmed liver tissue, most probably due to interference of the HO-1 pathway with CCl(4)-dependent metabolism via cytochrome P450 and heme overload-associated toxicity.
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Affiliation(s)
- Christian Eipel
- Institute of Experimental Surgery, University of Rostock, Rostock, Germany
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40
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Liu XM, Peyton KJ, Ensenat D, Wang H, Hannink M, Alam J, Durante W. Nitric oxide stimulates heme oxygenase-1 gene transcription via the Nrf2/ARE complex to promote vascular smooth muscle cell survival. Cardiovasc Res 2007; 75:381-9. [PMID: 17408602 PMCID: PMC1994113 DOI: 10.1016/j.cardiores.2007.03.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2006] [Revised: 03/05/2007] [Accepted: 03/06/2007] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Previous studies from our laboratory and others found that NO is a potent inducer of heme oxygenase-1 (HO-1) gene transcription in vascular smooth muscle cells (SMC), however, the mechanism responsible for the induction of HO-1 gene expression has not been elucidated. In the present study, we determined the signaling pathway responsible for the induction of HO-1 and its biological significance. METHODS Cultured rat aortic SMC were exposed to nitrosative stress by treating cells with various NO donors or with inflammatory cytokines. RESULTS Nitrosative stress stimulated an increase in HO-1 mRNA expression and promoter activity in vascular SMC. However, mutation of the antioxidant response element (ARE) in the HO-1 promoter or overexpression of a dominant-negative mutant of NF-E2-related factor-2 (Nrf2) abrogated the activation by NO. Electromobility shift assays using an ARE probe detected a complex that was significantly increased in intensity by NO. In addition, the migration of this complex was retarded by using an antibody directed against Nrf2. NO also increased Nrf2 mRNA expression, total and nuclear Nrf2 levels, and the binding of Nrf2 to the HO-1 promoter. Finally, treatment of SMC with NO stimulated apoptosis that was increased by HO-1 inhibition. CONCLUSIONS These results demonstrate that nitrosative stress induces HO-1 gene transcription through the activation of the Nrf2/ARE complex to counteract NO-induced apoptosis of vascular SMC. The capacity of nitrosative stress to activate Nrf2 and stimulate HO-1 gene transcription may represent a critical adaptive response to maintain cell viability at sites of vascular inflammation and atherosclerosis.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Apoptosis/drug effects
- Cell Survival
- Cells, Cultured
- Electrophoresis, Polyacrylamide Gel
- Electrophoretic Mobility Shift Assay
- Gene Expression
- Heme Oxygenase-1/genetics
- Muscle, Smooth, Vascular
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/metabolism
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/immunology
- NF-E2-Related Factor 2/metabolism
- Nitric Oxide/metabolism
- Nitric Oxide Donors/pharmacology
- Nitrosation
- Promoter Regions, Genetic
- RNA, Messenger/analysis
- Rats
- Response Elements
- Transcription, Genetic
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Affiliation(s)
- Xiao-ming Liu
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Kelly J. Peyton
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030
| | - Diana Ensenat
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212
| | - Hong Wang
- Department of Pharmacology, Temple University, Philadelphia, PA 19140
| | - Mark Hannink
- Department of Biochemistry, University of Missouri, Columbia, Missouri 65212
| | - Jawed Alam
- Department of Molecular Genetics, Ochsner Clinic Foundation, New Orleans, LA 70121
| | - William Durante
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030
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Tanaka Y, Maher JM, Chen C, Klaassen CD. Hepatic ischemia-reperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats and mice. Mol Pharmacol 2007; 71:817-25. [PMID: 17151289 DOI: 10.1124/mol.106.029033] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Hepatic ischemia-reperfusion (IR) results in Kupffer cell activation and subsequent tumor necrosis factor (TNF) alpha release, leading to localized hepatic injury and remote organ dysfunction. Heme oxygenase (HO)-1 is an enzyme that is induced by various stimuli, including proinflammatory cytokines, and exerts antioxidative and anti-inflammatory functions. Up-regulation of HO-1 is known to protect against hepatic IR injury, but the effects of hepatic IR on the kidney are poorly understood. Thus, the purpose of this study was to determine whether hepatic IR and resultant Kupffer cell activation alters renal HO-1 expression. Male Sprague-Dawley rats and wild-type and NF-E2-related factor 2 (Nrf2)-null mice were subjected to 60 min of partial hepatic ischemia, and at various times thereafter, blood, liver, and kidneys were collected. After reperfusion, 1) creatinine clearance decreased; 2) HO-1 mRNA and protein expression in liver and kidney markedly increased; 3) renal NAD(P)H: quinone oxidoreductase 1 mRNA expression was induced; 4) serum TNFalpha levels increased; 5) Nrf2 translocation into the nucleus of renal tissue increased; and 6) renal and urinary 15-deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) levels increased. Kupffer cell depletion by pretreating with gadolinium chloride 1) attenuated increased mRNA expression of HO-1 in kidney; 2) attenuated the increase in TNFalpha; 3) inhibited the increase in Nrf2 nuclear translocation; and 4) tended to attenuate renal 15-d-PGJ2 levels. Whereas renal HO-1 mRNA expression increased in wild-type mice, it was attenuated in Nrf2-null mice. These results suggest that renal HO-1 is induced via Nrf2 to protect the kidney from remote organ injury after hepatic IR.
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Affiliation(s)
- Yuji Tanaka
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7417, USA
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Abstract
Carbon monoxide (CO) is an endogenously derived gas formed from the breakdown of heme by the enzyme heme oxygenase. Although long considered an insignificant and potentially toxic waste product of heme catabolism, CO is now recognized as a key signaling molecule that regulates numerous cardiovascular functions. Interestingly, alterations in CO synthesis are associated with many cardiovascular disorders, including atherosclerosis, septic shock, hypertension, metabolic syndrome, and ischemia-reperfusion injury. Significantly, restoration of physiologic CO levels exerts a beneficial effect in many of these settings, suggesting a crucial role for CO in maintaining cardiovascular homeostasis. In this review, we outline the actions of CO in the cardiovascular system and highlight this gas as a potential therapeutic target in treating a multitude of cardiovascular disorders.
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Affiliation(s)
- William Durante
- Department of Medical Pharmacology and Physiology, M409 Medical Sciences Building, School of Medicine, University of Missouri-Columbia, One Hospital Drive, Columbia, MO 65212, USA.
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Tamion F, Richard V, Renet S, Thuillez C. Protective effects of heme-oxygenase expression against endotoxic shock: inhibition of tumor necrosis factor-alpha and augmentation of interleukin-10. ACTA ACUST UNITED AC 2006; 61:1078-84. [PMID: 17099512 DOI: 10.1097/01.ta.0000239359.41464.ef] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Heme-oxygenase (HO)-1 acts as an inducible defense against oxidative stress and could play an important role in inflammation models, providing protection against oxidative stress and systemic inflammatory response. The objective of this study was to improve the role of HO-1 on systemic inflammatory response in an endotoxic shock model. METHODS Five groups of animals were used: control group; lipopolysaccharide (LPS) group, animals received LPS 5 mg/kg; hemin + LPS group, animals received pretreatment with hemin, used to induce HO-1 expression; Zn-PP group, animals received Zn-PP, a specific inhibitor of HO-1 activity and hemin group. At the end of the experiment, tissue and blood samples were isolated for the measurement of HO-1 mRNA expression, biochemical measurements, and cytokine measurements. RESULTS HO-1 messenger RNA expression and protein were induced to a larger extent in LPS group in distal organs. Hemin pretreatment induced a significant decrease oxidative stress and tumor necrosis factor-alpha plasma levels with a significant increase of interleukin-10 plasma levels. Pulmonary injury was markedly limited after hemin. Onset of lethality in LPS group occurred at H6, and was delayed until H10 with hemin. Inhibition of HO-1 activity by Zn-PP administration abolished the beneficial effect of hemin-pretreatment. CONCLUSIONS Early HO-1 expression may modulate systemic inflammatory response and limit end-organ injury in endotoxic shock model.
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Affiliation(s)
- Fabienne Tamion
- Institut National de la Santé et de la Recherche Médicale, Rouen University Hospital, Rouen, France.
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Moreto V, Stabile AM, Antunes-Rodrigues J, Carnio EC. Role of heme-oxygenase pathway on vasopressin deficiency during endotoxemic shock-like conditions. Shock 2006; 26:472-6. [PMID: 17047517 DOI: 10.1097/01.shk.0000230301.86139.6a] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The septic shock is characterized by decrease in median arterial pressure; many researchers have been related a deficiency in vasopressin release during the septic shock. Lipopolysaccharide administration is used to induce septic shock model in animals. We investigated the heme-oxygenase (HO) inhibition during the endotoxemic shock-like conditions. The LPS administration induced a significant decrease in MAP (-15.4 +/- 1.2 mmHg at second hour, -25.8 +/- 8.7 mmHg at fourth hour, and -22.3 +/- 8.6 mmHg at sixth hour) with a concomitant increase in heart rate (486.3 +/- 55.0, 531.8 +/- 53.8, and 510.0 +/- 55.3 bpm, respectively), a significant decrease in diuresis (from 1.1 +/- 0.7 to 0.4 +/- 0.3/100g body weight at fourth hour), and a transitory decrease in body temperature (from 37.0 +/- 0.5 to 35.4 +/- 0.8 degrees C at second hour). An increase in plasma arginine vasopressin (AVP) concentration (from 3.2 +/- 0.9 to 19.0 +/- 5.7 pg/mL at the first hour) occurred in these animals and was present for 2 h after LPS administration, returning close to basal levels thereafter and remaining unchanged until the end of the experiment. When LPS was combined with the i.c.v. administration of HO inhibitor, we observed a sustained increase in plasma AVP concentration, attenuation in the drop of MAP, and increase in antidiuresis induced by LPS treatment. These data suggest that central HO pathway may activate a control mechanism that attenuates AVP secretion during endotoxemia and may consequently regulate the MAP and diuretic output.
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Affiliation(s)
- Viviana Moreto
- Departamento de Enfermagem Geral e Especializada, Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
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Fredenburgh LE, Perrella MA, Mitsialis SA. The role of heme oxygenase-1 in pulmonary disease. Am J Respir Cell Mol Biol 2006; 36:158-65. [PMID: 16980551 PMCID: PMC2176110 DOI: 10.1165/rcmb.2006-0331tr] [Citation(s) in RCA: 164] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Heme oxygenase (HO)-1, the inducible isoform of heme oxygenase, is a cytoprotective enzyme that plays a central role in the defense against oxidative and inflammatory insults in the lung. HO-1 catalyzes the degradation of heme, a potent oxidant, into biliverdin, iron, and carbon monoxide (CO). These downstream products of heme catabolism have recently been found to mediate the antioxidant, antiapoptotic, antiproliferative, vasodilatory, and anti-inflammatory properties of HO-1. Although absence of HO-1 is rare in humans, a number of HO-1 promoter polymorphisms have been identified that may influence HO-1 expression in vivo and lead to disease states. This review will summarize studies that implicate HO-1 and heme metabolites in the pathophysiology of pulmonary disease and discuss recent advances in the therapeutic applications of HO-1.
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Affiliation(s)
- Laura E Fredenburgh
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
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Kwak HJ, Park KM, Lee S, Lim HJ, Go SH, Eom SM, Park HY. Preconditioning with low concentration NO attenuates subsequent NO-induced apoptosis in vascular smooth muscle cells via HO-1-dependent mitochondrial death pathway. Toxicol Appl Pharmacol 2006; 217:176-84. [PMID: 17027882 DOI: 10.1016/j.taap.2006.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2006] [Revised: 07/28/2006] [Accepted: 08/28/2006] [Indexed: 11/16/2022]
Abstract
Nitric oxide (NO) signaling pathways are important in both the maintenance of vascular homeostasis and disease progression. Overproduction of NO has been associated with ischemia/reperfusion (I/R) injury. Growing evidences suggest that NO preconditioning has cytoprotective effects against I/R injury. However, the mechanism with which NO mediates these effects remains to be elucidated. The purpose of this study was to examine the mechanism of how NO preconditioning inhibits subsequent NO-induced apoptosis in vascular smooth muscle cells (VSMC), specifically focusing on heme oxygenase-1 (HO-1). According to our data, sodium nitroprusside (SNP) increased HO-1 expression in a concentration dependent manner. Preconditioning with low concentration SNP (0.3mM) inhibited subsequent high concentration SNP (1.5mM)-induced apoptosis, and this effect was reversed by the HO-1 inhibitor SnPP. Low concentration SNP-mediated protection involved p38 kinase inactivation and increased Bcl-2 expression. Furthermore, mitochondrial membrane potential was concomitantly increased with decreased expressions of Bax, Apaf-1, and activity of caspase-3, which was reversed by SnPP treatment. Our results show that low concentration SNP preconditioning suppresses subsequent high concentration SNP-induced apoptosis by inhibiting p38 kinase and mitochondrial death pathway via HO-1-dependent mechanisms in VSMC.
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MESH Headings
- Animals
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Apoptosis/drug effects
- Apoptosis Regulatory Proteins/metabolism
- Cell Survival/drug effects
- Cells, Cultured
- Dose-Response Relationship, Drug
- Heme Oxygenase (Decyclizing)/metabolism
- Male
- Membrane Potential, Mitochondrial/drug effects
- Mitochondria/drug effects
- Mitochondria/metabolism
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Nitric Oxide/metabolism
- Nitric Oxide Donors/pharmacology
- Nitroprusside/pharmacology
- Phosphorylation
- Rats
- Rats, Wistar
- Up-Regulation/drug effects
- p38 Mitogen-Activated Protein Kinases/metabolism
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Affiliation(s)
- Hyun-Jeong Kwak
- Division of Cardiovascular Diseases, Center for Biomedical Sciences, National Institutes of Health, Nokbun-dong, Eunpyung-gu, Seoul 122-701, Republic of Korea
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Palma MD, Aller MA, Vara E, Nava MP, Garcia C, Arias-Diaz J, Balibrea JL, Arias J. Portal hypertension produces an evolutive hepato-intestinal pro- and anti-inflammatory response in the rat. Cytokine 2006; 31:213-26. [PMID: 15950486 DOI: 10.1016/j.cyto.2005.04.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2004] [Revised: 12/12/2004] [Accepted: 04/27/2005] [Indexed: 01/29/2023]
Abstract
An inflammatory etiopathogeny can be suggested in portal hypertensive enteropathy since infiltration of the intestinal wall by mononuclear cells has been described in this condition. This work was carried out with the intention of shedding light on this matter. Male Wistar rats were divided into 4 control groups and 4 groups with partial portal vein ligation at 1, 2, 3 and 15 months. TNF-alpha, IL-1beta and IL-10 were quantified in liver and ileum by ELISA. CO and NO were measured in splanchnic and systemic vein by spectrophotometry and Griess reaction, respectively. Expression of constitutive and inducible isoforms of NO and HO were assayed by Western blot in liver and ileum. An increased hepatic release of proinflammatory mediators (TNF-alpha, IL-1beta and NO) associated with intestinal release of anti-inflammatory mediators (IL-10, CO) occurs in an early evolutive phase (1 month) of experimental portal hypertension. On the contrary, in the long-term (15 months), the increase in the intestinal release of proinflammatory mediators (TNF-alpha, IL-1beta) is associated with an increase in the hepatic release of anti-inflammatory mediators (IL-10, CO). These results suggest that experimental prehepatic portal hypertension presents changes in the serum and tissular (liver and small bowel) concentrations of mediators which are considered as pro- and anti-inflammatory.
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Lo WC, Lu PJ, Ho WY, Hsiao M, Tseng CJ. Induction of heme oxygenase-1 is involved in carbon monoxide-mediated central cardiovascular regulation. J Pharmacol Exp Ther 2006; 318:8-16. [PMID: 16565166 DOI: 10.1124/jpet.105.099051] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Carbon monoxide (CO) has been identified as an endogenous biological messenger in the brain. Heme oxygenase (HO) catalyzes the metabolism of heme to CO and biliverdin. Previously, we have shown the involvement of CO in central cardiovascular regulation, baroreflex modulation, and glutaminergic neuro-transmission in the nucleus tractus solitarii (NTS) of rats. In this study, we examined which HO isoform could be induced after hemin injection in the NTS. We also investigated their in situ distributions in the NTS after induction. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of hemin (1 nmol), a heme molecule cleaved by HO to yield CO, produced significant decrease in blood pressure and heart rate. These cardiovascular effects of hemin were attenuated by prior administration of HO inhibitor zinc protoporphyrin IX (ZnPPIX). Microinjection of hemin into NTS resulted in significant induction of HO-1 protein expression in situ. Pretreatment of ZnPPIX significantly inhibited the HO-1 induction after hemin injection. No significant changes of HO-2 expression were found after hemin injection and ZnPPIX pretreatment. The in situ inductions of the HO-1 protein expression were further confirmed to be in glial cells and neurons after hemin injections into the NTS. These results indicated HO-1 but not HO-2 might be responsible for the generation of CO and contribute to central control of cardiovascular effects.
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Affiliation(s)
- Wan-Chen Lo
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, Kaohsiung, Taiwan
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Sharma S, Dewald O, Adrogue J, Salazar RL, Razeghi P, Crapo JD, Bowler RP, Entman ML, Taegtmeyer H. Induction of antioxidant gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species. Free Radic Biol Med 2006; 40:2223-31. [PMID: 16785036 DOI: 10.1016/j.freeradbiomed.2006.02.019] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2005] [Revised: 01/18/2006] [Accepted: 02/28/2006] [Indexed: 02/02/2023]
Abstract
Ischemia and reperfusion (I/R) are characterized by oxidative stress as well as changes in the antioxidant enzymes of the heart. However, little is known about the transcriptional regulation of myocardial antioxidant enzymes in repetitive I/R and hibernating myocardium. In a mouse model of ischemic cardiomyopathy induced by repetitive I/R, we postulated that induction of antioxidant gene expression was dependent on reactive oxygen species (ROS). Repetitive closed-chest I/R (15 min) was performed daily in C57/BL6 mice and in mice overexpressing extracellular superoxide dismutase (EC-SOD). Antioxidant enzyme expression was measured at 3, 5, 7, and 28 days of repetitive I/R as well as 15 and 30 days after discontinuation of I/R. In order to determine whether ROS directly modulates antioxidant gene expression, transcript levels were measured in cardiomyocytes exposed to hydrogen peroxide. Repetitive I/R caused an early and sustained increase in glutathione peroxidase (GPX) transcript levels, while heme oxygenase-1 (HO-1) expression increased only after 7 days of repetitive I/R. Overexpression of EC-SOD prevented the upregulation of GPX and HO-1 transcript levels by repetitive I/R, suggesting that both genes are regulated by ROS. However, while HO-1 transcript levels increased in cardiomyocytes exposed to hydrogen peroxide, oxidative stress failed to induce the expression of GPX implying that ROS regulates GPX transcript levels only indirectly in repetitive I/R. In conclusion, repetitive I/R was associated with an early upregulation of GPX expression as well as a delayed increase of HO-1 transcript levels in the heart. The induction of both antioxidant genes was dependent on ROS, suggesting that alterations in redox balance mediate not only tissue injury but also components of "programmed cell survival" in hibernating myocardium.
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Affiliation(s)
- Saumya Sharma
- Cardiology, The University of Texas Houston Medical School, USA
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Kim HJ, Tsoy I, Park MK, Lee YS, Lee JH, Seo HG, Chang KC. Iron released by sodium nitroprusside contributes to heme oxygenase-1 induction via the cAMP-protein kinase A-mitogen-activated protein kinase pathway in RAW 264.7 cells. Mol Pharmacol 2006; 69:1633-40. [PMID: 16439612 DOI: 10.1124/mol.105.020487] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Nitric oxide (NO) is a potent inducer of heme oxygenase (HO)-1, and NO-induced HO-1 expression is dependent on the cGMP-signaling pathway. Sodium nitroprusside (SNP) produces NO and iron. However, it is unclear whether NO is exclusively responsible for induction of HO-1 by SNP in RAW 264.7 cells. We tested our hypothesis that iron may contribute more to the SNP induction of HO-1 than does NO by comparing the HO-1 protein level and the production of NO in RAW 264.7 cells treated with SNP and S-nitroso-N-acetyl-DL-penicillamine (SNAP). Although SNP induced less NO production than SNAP, SNP induced the production of more HO-1 protein than did SNAP. Deferoxamine (DFO) decreased SNP- but not SNAP-induced HO-1 expression but did not decrease the production of NO. SNP-induced HO-1 was significantly inhibited by specific protein kinase A (PKA) inhibitors or an antagonist of cAMP but not by guanylyl cyclase inhibitors. Exogenous iron (ferric ammonium citrate or ferricyanide) and forskolin increased the level of HO-1, which was inhibited by PKA inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89). These results indicate that iron and cAMP, but not cGMP, play crucial roles in the induction of HO-1 in RAW 264.7 cells. Moreover, DFO and inhibitors of extracellular signal-related kinases 1/2 or c-Jun NH(2)-terminal kinase inhibited HO-1 production induced by SNP. This study illustrates that iron rather than NO from SNP contributes to HO-1 induction. Therefore, studies on the effects of SNP should consider the role of iron in some biological functions. We concluded that iron released by SNP contributes to HO-1 induction via the cAMP-PKA-mitogen-activated protein kinase pathway.
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Affiliation(s)
- Hye Jung Kim
- Department of Pharmacology, College of Medicine, Gyeongsang National University, 92 Chilam-dong, Jinju, South Korea
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