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Petushkova AI, Zamyatnin AA. Redox-Mediated Post-Translational Modifications of Proteolytic Enzymes and Their Role in Protease Functioning. Biomolecules 2020; 10:biom10040650. [PMID: 32340246 PMCID: PMC7226053 DOI: 10.3390/biom10040650] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 12/13/2022] Open
Abstract
Proteolytic enzymes play a crucial role in metabolic processes, providing the cell with amino acids through the hydrolysis of multiple endogenous and exogenous proteins. In addition to this function, proteases are involved in numerous protein cascades to maintain cellular and extracellular homeostasis. The redox regulation of proteolysis provides a flexible dose-dependent mechanism for proteolytic activity control. The excessive reactive oxygen species (ROS) and reactive nitrogen species (RNS) in living organisms indicate pathological conditions, so redox-sensitive proteases can swiftly induce pro-survival responses or regulated cell death (RCD). At the same time, severe protein oxidation can lead to the dysregulation of proteolysis, which induces either protein aggregation or superfluous protein hydrolysis. Therefore, oxidative stress contributes to the onset of age-related dysfunction. In the present review, we consider the post-translational modifications (PTMs) of proteolytic enzymes and their impact on homeostasis.
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Affiliation(s)
- Anastasiia I. Petushkova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Andrey A. Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- Correspondence:
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Gaspar D, Peixoto R, De Pieri A, Striegl B, Zeugolis DI, Raghunath M. Local pharmacological induction of angiogenesis: Drugs for cells and cells as drugs. Adv Drug Deliv Rev 2019; 146:126-154. [PMID: 31226398 DOI: 10.1016/j.addr.2019.06.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 05/12/2019] [Accepted: 06/16/2019] [Indexed: 12/12/2022]
Abstract
The past decades have seen significant advances in pro-angiogenic strategies based on delivery of molecules and cells for conditions such as coronary artery disease, critical limb ischemia and stroke. Currently, three major strategies are evolving. Firstly, various pharmacological agents (growth factors, interleukins, small molecules, DNA/RNA) are locally applied at the ischemic region. Secondly, preparations of living cells with considerable bandwidth of tissue origin, differentiation state and preconditioning are delivered locally, rarely systemically. Thirdly, based on the notion, that cellular effects can be attributed mostly to factors secreted in situ, the cellular secretome (conditioned media, exosomes) has come into the spotlight. We review these three strategies to achieve (neo)angiogenesis in ischemic tissue with focus on the angiogenic mechanisms they tackle, such as transcription cascades, specific signalling steps and cellular gases. We also include cancer-therapy relevant lymphangiogenesis, and shall seek to explain why there are often conflicting data between in vitro and in vivo. The lion's share of data encompassing all three approaches comes from experimental animal work and we shall highlight common technical obstacles in the delivery of therapeutic molecules, cells, and secretome. This plethora of preclinical data contrasts with a dearth of clinical studies. A lack of adequate delivery vehicles and standardised assessment of clinical outcomes might play a role here, as well as regulatory, IP, and manufacturing constraints of candidate compounds; in addition, completed clinical trials have yet to reveal a successful and efficacious strategy. As the biology of angiogenesis is understood well enough for clinical purposes, it will be a matter of time to achieve success for well-stratified patients, and most probably with a combination of compounds.
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Affiliation(s)
- Diana Gaspar
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Rita Peixoto
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Andrea De Pieri
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Proxy Biomedical Ltd., Coilleach, Spiddal, Galway, Ireland
| | - Britta Striegl
- Competence Centre Tissue Engineering for Drug Development (TEDD), Centre for Cell Biology & Tissue Engineering, Institute for Chemistry and Biotechnology, Zurich University of Applied Sciences, Zurich, Switzerland
| | - Dimitrios I Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland; Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Michael Raghunath
- Competence Centre Tissue Engineering for Drug Development (TEDD), Centre for Cell Biology & Tissue Engineering, Institute for Chemistry and Biotechnology, Zurich University of Applied Sciences, Zurich, Switzerland.
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Huang LY, Yen IC, Tsai WC, Ahmetaj-Shala B, Chang TC, Tsai CS, Lee SY. Rhodiola crenulata Attenuates High Glucose Induced Endothelial Dysfunction in Human Umbilical Vein Endothelial Cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:1201-1216. [DOI: 10.1142/s0192415x17500665] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Rhodiola crenulata root extract (RCE), a traditional Chinese medicine, has been shown to regulate glucose and lipid metabolism via the AMPK pathway in high glucose (HG) conditions. However, the effect of RCE on HG-induced endothelial dysfunction remains unclear. The present study was designed to examine the effects and mechanisms of RCE against hyperglycemic insult in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without RCE and then exposed to 33[Formula: see text]mM HG medium. The cell viability, nitrite production, oxidative stress markers, and vasoactive factors, as well as the mechanisms underlying RCE action, were then investigated. We found that RCE significantly improved cell death, nitric oxide (NO) defects, and oxidative stress in HG conditions. In addition, RCE significantly decreased the HG-induced vasoactive markers, including endothelin-1 (ET-1), fibronectin, and vascular endothelial growth factor (VEGF). However, the RCE-restored AMPK-Akt-eNOS-NO axis and cell viability were abolished by the presence of an AMPK inhibitor. These findings suggested that the protective effects of RCE were associated with the AMPK-Akt-eNOS-NO signaling pathway. In conclusion, we showed that RCE protected endothelial cells from hyperglycemic insult and demonstrated its potential for use as a treatment for endothelial dysfunction in diabetes mellitus.
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Affiliation(s)
- Li-Yen Huang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - I-Chuan Yen
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Cheng Tsai
- Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | | | - Tsu-Chung Chang
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Sung Tsai
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan
- Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed General Forces General Hospital, Taoyuan, Taiwan
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Shih-Yu Lee
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
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Bahnson ESM, Vavra AK, Flynn ME, Vercammen JM, Jiang Q, Schwartz AR, Kibbe MR. Long-term effect of PROLI/NO on cellular proliferation and phenotype after arterial injury. Free Radic Biol Med 2016; 90:272-86. [PMID: 26627935 PMCID: PMC4698201 DOI: 10.1016/j.freeradbiomed.2015.11.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 11/20/2015] [Accepted: 11/23/2015] [Indexed: 10/22/2022]
Abstract
Vascular interventions are associated with high failure rates from restenosis secondary to negative remodeling and neointimal hyperplasia. Periadventitial delivery of nitric oxide (NO) inhibits neointimal hyperplasia, preserving lumen patency. With the development of new localized delivery vehicles, NO-based therapies remain a promising therapeutic avenue for the prevention of restenosis. While the time course of events during neointimal development has been well established, a full characterization of the impact of NO donors on the cells that comprise the arterial wall has not been performed. Thus, the aim of our study was to perform a detailed assessment of proliferation, cellularity, inflammation, and phenotypic cellular modulation in injured arteries treated with the short-lived NO donor, PROLI/NO. PROLI/NO provided durable inhibition of neointimal hyperplasia for 6 months after arterial injury. PROLI/NO inhibited proliferation and cellularity in the media and intima at all of the time points studied. However, PROLI/NO caused an increase in adventitial proliferation at 2 weeks, resulting in increased cellularity at 2 and 8 weeks compared to injury alone. PROLI/NO promoted local protein S-nitrosation and increased local tyrosine nitration, without measurable systemic effects. PROLI/NO predominantly inhibited contractile smooth muscle cells in the intima and media, and had little to no effect on vascular smooth muscle cells or myofibroblasts in the adventitia. Finally, PROLI/NO caused a delayed and decreased leukocyte infiltration response after injury. Our results show that a short-lived NO donor exerts durable effects on proliferation, phenotype modulation, and inflammation that result in long-term inhibition of neointimal hyperplasia.
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Affiliation(s)
- Edward S M Bahnson
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States
| | - Ashley K Vavra
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States
| | - Megan E Flynn
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States
| | - Janet M Vercammen
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States
| | - Qun Jiang
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States
| | - Amanda R Schwartz
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States
| | - Melina R Kibbe
- Division of Vascular Surgery, Northwestern University, Chicago, IL, United States; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, United States; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States.
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5
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Morales RC, Bahnson ESM, Havelka GE, Cantu-Medellin N, Kelley EE, Kibbe MR. Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide. Redox Biol 2015; 4:226-33. [PMID: 25617803 PMCID: PMC4803798 DOI: 10.1016/j.redox.2015.01.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 01/08/2015] [Accepted: 01/12/2015] [Indexed: 11/28/2022] Open
Abstract
Background Nitric oxide (•NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2•−) regulates cellular proliferation, and •NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that •NO differentially regulates SOD-1 based on sex. Materials and methods Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O2•− levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±•NO treatment and SOD-1 protein levels were examined by Western blot. Results In vitro, male VSMC have higher O2•− levels and lower SOD − 1 activity at baseline compared to female VSMC (P < 0.05). •NO decreased O2•− levels and increased SOD − 1 activity in male (P<0.05) but not female VSMC. •NO also increased sod− 1 gene expression and SOD − 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but •NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females. Conclusions Our results provide evidence that regulation of the redox environment at baseline and following exposure to •NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which •NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents.
The baseline redox environment in the vascular is sex-dependent. Nitric oxide differentially affects the vascular redox environment between the sexes. Nitric oxide decreases superoxide (O2.) levels, by increasing SOD-1 activity, sod1 gene expression and SOD-1 protein levels in male vascular smooth muscle cells, but not in females. Sex-based differential redox regulation may be one mechanism by which is more effective at inhibiting neointimal hyperplasia in male versus female rodents.
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Affiliation(s)
- Rommel C Morales
- Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA
| | - Edward S M Bahnson
- Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA
| | - George E Havelka
- Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA
| | | | - Eric E Kelley
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Melina R Kibbe
- Division of Vascular Surgery, Northwestern University, Chicago, IL, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
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Bahnson ESM, Koo N, Cantu-Medellin N, Tsui AY, Havelka GE, Vercammen JM, Jiang Q, Kelley EE, Kibbe MR. Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall. Nitric Oxide 2014; 44:8-17. [PMID: 25460325 DOI: 10.1016/j.niox.2014.10.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/20/2014] [Accepted: 10/27/2014] [Indexed: 12/29/2022]
Abstract
Superoxide (O2(•-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((•)NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether (•)NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (•)NO exerts cell-specific, differential modulation of O2(•-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (•)NO-dependent inhibition of neointimal hyperplasia. In vivo, (•)NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (•)NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2(•-) levels. Lastly, to determine the role of SOD-1 in (•)NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without (•)NO. Interestingly, (•)NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2(•-) by (•)NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (•)NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia.
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Affiliation(s)
- Edward S M Bahnson
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Nathaniel Koo
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | | | - Aaron Y Tsui
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - George E Havelka
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Janet M Vercammen
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Qun Jiang
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA
| | - Eric E Kelley
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Melina R Kibbe
- Division of Vascular Surgery, Northwestern University, Chicago, Illinois, USA; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, Illinois, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
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Alagem-Shafir M, Kivovich E, Tzchori I, Lanir N, Falah M, Flugelman M, Dinnar U, Beyar R, Lotan N, Sivan S. The formation of an anti-restenotic/anti-thrombotic surface by immobilization of nitric oxide synthase on a metallic carrier. Acta Biomater 2014; 10:2304-12. [PMID: 24389316 DOI: 10.1016/j.actbio.2013.12.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 12/13/2013] [Accepted: 12/18/2013] [Indexed: 12/20/2022]
Abstract
Coronary stenosis due to atherosclerosis, the primary cause of coronary artery disease, is generally treated by balloon dilatation and stent implantation, which can result in damage to the endothelial lining of blood vessels. This leads to the restenosis of the lumen as a consequence of migration and proliferation of smooth muscle cells (SMCs). Nitric oxide (NO), which is produced and secreted by vascular endothelial cells (ECs), is a central anti-inflammatory and anti-atherogenic player in the vasculature. The goal of the present study was to develop an enzymatically active surface capable of converting the prodrug l-arginine, to the active drug, NO, thus providing a targeted drug delivery interface. NO synthase (NOS) was chemically immobilized on the surface of a stainless steel carrier with preservation of its activity. The ability of this functionalized NO-producing surface to prevent or delay processes involved in restenosis and thrombus formation was tested. This surface was found to significantly promote EC adhesion and proliferation while inhibiting that of SMCs. Furthermore, platelet adherence to this surface was markedly inhibited. Beyond the application considered here, this approach can be implemented for the local conversion of any systemically administered prodrug to the active drug, using catalysts attached to the surface of the implant.
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Feng X, Sun T, Bei Y, Ding S, Zheng W, Lu Y, Shen P. S-nitrosylation of ERK inhibits ERK phosphorylation and induces apoptosis. Sci Rep 2013; 3:1814. [PMID: 23657295 PMCID: PMC3648801 DOI: 10.1038/srep01814] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 04/23/2013] [Indexed: 01/10/2023] Open
Abstract
Extracellular signal-regulated kinase (ERK) belongs to the mitogen-activated protein kinases (MAPK) superfamily. Aberrant upregulation and activation of ERK cascades may often lead to tumor cell development. However, how ERK is involved in tumor progression is yet to be defined. In current study, we described that ERK undergoes S-nitrosylation by nitric oxide (NO). ERK S-nitrosylation inhibits its phosphorylation and triggers apoptotic program as verified by massive apoptosis in fluorescence staining. The proapoptotic effect of NO induced S-nitrosylation is reversed by NO scavenger Haemoglobin (HB). Furthermore, an S-nitrosylation dead ERK mutant C183A also demolishes the proapoptotic potential of NO and favors cell survival. Therefore, Cys183 might be a potential S-nitrosylation site in ERK. In addition, S-nitrosylation is a general phenomenon that regulates ERK activity. These findings identify a novel link between NO-mediated S-nitrosylation and ERK regulation, which provide critical insights into the control of apoptosis and tumor development.
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Affiliation(s)
- Xiujing Feng
- State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210093, China
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Cheng G, Kong RH, Zhang LM, Zhang JN. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 2013; 167:699-719. [PMID: 23003569 DOI: 10.1111/j.1476-5381.2012.02025.x] [Citation(s) in RCA: 251] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Traumatic brain injury (TBI) is a major health and socioeconomic problem throughout the world. It is a complicated pathological process that consists of primary insults and a secondary insult characterized by a set of biochemical cascades. The imbalance between a higher energy demand for repair of cell damage and decreased energy production led by mitochondrial dysfunction aggravates cell damage. At the cellular level, the main cause of the secondary deleterious cascades is cell damage that is centred in the mitochondria. Excitotoxicity, Ca(2+) overload, reactive oxygen species (ROS), Bcl-2 family, caspases and apoptosis inducing factor (AIF) are the main participants in mitochondria-centred cell damage following TBI. Some preclinical and clinical results of mitochondria-targeted therapy show promise. Mitochondria- targeted multipotential therapeutic strategies offer new hope for the successful treatment of TBI and other acute brain injuries.
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Affiliation(s)
- Gang Cheng
- Neurosurgical Department, PLA Navy General Hospital, Beijing, China
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Abstract
After iron, zinc is the most abundant essential trace metal. Intracellular zinc ([Zn]i) is maintained across a wide range of cells and species in a tight quota (100 to 500 μM) by a dynamic process of transport, intracellular vesicular storage, and binding to a large number of proteins (estimated at 3-10% of human proteome). As such, zinc is an integral component of numerous metalloenzymes, structural proteins, and transcription factors. It is generally assumed that a vanishingly small component of [Zn]i, referred to as free or labile zinc, and operationally defined as the pool sensitive to chelation (by agents such as N, N, N’, N’-tetrakis [2-pyridylmethyl] ethylenediamine [TPEN]) and capable of detection by a variety of chemical and genetic sensors, participates in signal transduction pathways. Zinc deficiencies, per se, can arise from acquired (malnutrition, alcoholism) or genetic (mutations in molecules affecting zinc homeostasis, the informative and first example being acrodermatitis enteropathica) factors or as a component of various diseases (e.g., sickle cell disease, cystic fibrosis, sepsis). Hypozincemia has profound effects on developing humans, and all facets of physiological function (neuronal, endocrine, immunological) are affected, although considerably less is known regarding cardiovascular pathophysiology. In this review, we provide an update on current knowledge of molecular and cellular aspects of zinc homeostasis and then focus on implications of zinc signaling in pulmonary endothelium as it relates to programmed cell death, altered contractility, and septic and aseptic injury to this segment of the lung.
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Affiliation(s)
- Kalidasan Thambiayya
- Department of Bioengineering, University of Pittsburgh and University of Pittsburgh School of Medicine and Graduate School Public Health, Pittsburgh, Pennsylvania, USA
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Wang K, Lin B. Pathophysiological Significance of Hepatic Apoptosis. ISRN HEPATOLOGY 2012; 2013:740149. [PMID: 27335822 PMCID: PMC4890876 DOI: 10.1155/2013/740149] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Accepted: 12/13/2012] [Indexed: 12/19/2022]
Abstract
Apoptosis is a classical pathological feature in liver diseases caused by various etiological factors such as drugs, viruses, alcohol, and cholestasis. Hepatic apoptosis and its deleterious effects exacerbate liver function as well as involvement in fibrosis/cirrhosis and carcinogenesis. An imbalance between apoptotic and antiapoptotic capabilities is a prominent characteristic of liver injury. The regulation of apoptosis and antiapoptosis can be a pivotal step in the treatment of liver diseases.
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Affiliation(s)
- Kewei Wang
- Departments of Surgery and Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Bingliang Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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Thambiayya K, Wasserloos K, Kagan VE, Stoyanovsky D, Pitt BR. A critical role for increased labile zinc in reducing sensitivity of cultured sheep pulmonary artery endothelial cells to LPS-induced apoptosis. Am J Physiol Lung Cell Mol Physiol 2012; 302:L1287-95. [PMID: 22523284 DOI: 10.1152/ajplung.00385.2011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We previously noted an important signaling role for decreased labile intracellular zinc ([ Zn ] (i)) in LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC) (Tang ZL, Wasserloos KJ, Liu X, Stitt MS, Reynolds IJ, Pitt BR, St Croix CM. Mol Cell Biochem 234-235: 211-217, 2002; Thambiayya K, Wasserloos KJ, Huang Z, Kagan VE, St Croix CM, Pitt BR. Am J Physiol Lung Cell Mol Physiol 300: L624-632, 2011). In the present study, we used small interfering RNA (siRNA) to important contributors of zinc homeostasis [ SLC39A14 or Zrt/Irt-like protein 14 (ZIP14), a zinc importer; metallothionein (MT), a zinc binding protein ] to define molecular pathways by which extracellular zinc or nitric oxide (NO) increase labile [ Zn ] (i) [ e.g., zinc-sensitive fluorophore (FluoZin-3) detectable and/or chelatable by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine ] and reduce the sensitivity of SPAEC to LPS. Addition of 10 μM zinc to serum-free medium of SPAEC increased [ Zn ] (i) and abolished LPS-induced apoptosis (e.g., increased annexin V binding). The increase in [ Zn ] (i) and the protective effect of extracellular zinc were sensitive to reduction in ZIP14 expression (by siRNA), but not affected by collectively knocking down major isoforms of sheep MT (sMT-Ia, -Ib, -Ic, and -II). Pretreatment of wild-type SPAEC with 250 μM of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased labile zinc in a relatively similar fashion to addition of extracellular zinc and reduced sensitivity of SPAEC to LPS-induced apoptosis (e.g., caspase-3/7 activation) in a N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine-sensitive fashion. The antiapoptotic effects of SNAP were insensitive to siRNA knockdown of ZIP14, but were abolished (along with SNAP-induced increase in [ Zn ] (i)) when SPAEC were pretreated with siRNA to sheep MT. Zinc was able to directly inhibit recombinant caspase-3 activity in an in vitro assay. Collectively, these data show that increases in labile [ Zn ] (i) are an important component of ZIP14- or NO-mediated resistance to LPS-induced apoptosis. Cytoprotection via ZIP14 appeared to be secondary to transcellular movement of extracellular zinc, whereas NO-mediated protection was secondary to S-nitrosation of MT and redistribution of [ Zn ] (i).
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Affiliation(s)
- Kalidasan Thambiayya
- Dept. Environmental and Occupational Health, Univ. of Pittsburgh Graduate School Public Health, Bridgeside Point Bldg., 100 Technology Dr., Ste. 555, Pittsburgh, PA 15219, USA
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13
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Inhibitory Effect of Ginsenoside Rg1 on Vascular Smooth Muscle Cell Proliferation Induced by PDGF-BB Is Involved in Nitric Oxide Formation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:314395. [PMID: 22474498 PMCID: PMC3304546 DOI: 10.1155/2012/314395] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 12/17/2011] [Indexed: 12/14/2022]
Abstract
Ginsenoside Rg1 (Rg1) has been reported to suppress the proliferation of vascular smooth muscle cells (VSMCs). This study aimed to observe the role of nitric oxide (NO) in Rg1-antiproliferative effect. VSMCs from the thoracic aorta of SD rats were cultured by tissue explant method, and the effect of Rg1 (20 mg·L−1, 60 mg·L−1, and 180 mg·L−1) on platelet-derived growth factor-BB (PDGF-BB)-induced proliferation was evaluated by MTT assay. The cell cycle was analyzed by flow cytometry. For probing the mechanisms, the content of NO in supernatant and cGMP level in VSMCs was measured by nitric oxide kit and cGMP radio-immunity kit, respectively; the expressions of protooncogene c-fos and endothelial NO synthase (eNOS) mRNA in the VSMCs were detected by real-time RT-PCR; the intracellular free calcium concentration ([Ca2+]i) was detected with Fura-2/AM-loaded VSMCs. Comparing with that in normal group, Rg1 180 mg·L−1 did not change the absorbance of MTT and cell percent of G0/G1, G2/M, and S phase in normal cells (P > 0.05). Contrarily, PDGF-BB could increase the absorbance of MTT (P < 0.01) and the percent of the S phase cells but decrease the G0/G1 phase cell percent in the cell cycle, accompanied with an upregulating c-fos mRNA expression (P < 0.01), which was reversed by additions of Rg1(20 mg·L−1, 60 mg·L−1, and 180 mg·L−1). Rg1 administration could also significantly increase the NO content in supernatant and the cGMP level in VSMCs, as well as the eNOS mRNA expression in the cells, in comparison of that in the group treated with PDGF-BB alone (P < 0.01). Furthermore, Rg1 caused a further increase in the elevated [Ca2+]i induced by PDGF-BB. It was concluded that Rg1 could inhibit the VSMC proliferation induced by PDGF-BB through restricting the G0/G1 phase to S-phase progression in cell cycle. The mechanisms may be related to the upregulation of eNOS mRNA and the increase of the formation of NO and cGMP.
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14
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Wang K, Brems JJ, Gamelli RL, Holterman AX. iNOS/NO signaling regulates apoptosis induced by glycochenodeoxycholate in hepatocytes. Cell Signal 2011; 23:1677-85. [DOI: 10.1016/j.cellsig.2011.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 06/06/2011] [Indexed: 10/18/2022]
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15
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Emond ZM, Kibbe MR. Clinical science review article: understanding the implications of diabetes on the vascular system. Vasc Endovascular Surg 2011; 45:481-9. [PMID: 21571777 DOI: 10.1177/1538574411408354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Patients with diabetes comprise an extremely complex subset of patients for the vascular surgeon. Often, they have numerous comorbidities that can further complicate matters. The diabetic environment is highly complex and the interplay of various diseases makes this an extremely challenging condition to manage. Knowing the mechanisms by which diabetes inflicts adverse microscopic changes in the vasculature allows the clinician to anticipate problems and minimize the heightened risks observed in diabetic patients undergoing surgery. In this review, we will illustrate how diabetes affects the vasculature and how the molecular and cellular derangements that occur in diabetic environments lead to these pathophysiologic consequences.
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Affiliation(s)
- Zachary M Emond
- Department of Surgery, University of Illinois at Chicago, IL, USA
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16
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Zhang LH, Luo T, Zhang C, Luo P, Jin X, Song CX, Gao RL. Anti-DNA antibody modified coronary stent for plasmid gene delivery: results obtained from a porcine coronary stent model. J Gene Med 2010; 13:37-45. [PMID: 21259407 DOI: 10.1002/jgm.1529] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 07/05/2010] [Accepted: 11/14/2010] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Previous work in our laboratory has demonstrated that the anti-DNA antibody-immobilized stent results in highly site-specific gene delivery in a rabbit carotid model. As a result of the similarity in the anatomy and physiology of the pig and human cardiovascular systems, the porcine coronary stent model was used in the present study to evaluate the site-specificity, efficiency and long-term therapeutic effect of this gene delivery system in pig coronary arteries. METHODS A reporter plasmid pEGFP (pEGFP-C1) was tethered on the antibody-immobilized stents and assessed for site-specificity and efficiency in a pig coronary stent model. Inducible nitric oxide synthase (NOS) cDNA (pcDNA3.1-iNOS) was tethered on the stent as a therapeutic gene to evaluate the site-specificity and long-term therapeutic effect of this novel gene delivery system for the inhibition of restenosis after coronary stenting for 28 days. RESULTS Both the pEGFP-C1 and pcDNA3.1-iNOS tethered stents achieved site-specific gene transfection without distal spreading in the porcine coronary model. The overall GFP transfection efficiency was 2.6 ± 0.9% of the total cells, whereas the neointimal transfection was more than 6%. Histology and morphology studies showed no significant artery stenosis and intimal proliferation for 28 days after coronary stenting using pcDNA3.1-iNOS tethered stents. CONCLUSIONS For the first time, we report the successful use of anti-DNA antibody-immobilized stent as plasmid gene delivery system that possess high efficiency and site-specificity in a porcine coronary stent model. The novel system showed long-term therapeutic effects on the inhibition of restenosis when pcDNA3.1-iNOS was tethered on the stent.
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Affiliation(s)
- Lin-Hua Zhang
- Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, China
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17
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Li H, Cao R, Wasserloos KJ, Bernal P, Liu ZQ, Pitt BR, St Croix CM. Nitric oxide and zinc homeostasis in pulmonary endothelium. Ann N Y Acad Sci 2010; 1203:73-8. [PMID: 20716286 DOI: 10.1111/j.1749-6632.2010.05558.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We have shown that zinc-thiolate moieties of the metal binding protein metallothionein (MT) are critical targets for nitric oxide (NO) with resultant increases in intracellular labile zinc. Such an NO-MT-Zn signaling pathway appears to participate in important cardiovascular functions associated with biosynthesis of NO including hypoxic vasoconstriction in the lung. Although downstream effector signaling molecules and critical contractile targets remain unclear, current investigations reveal a contributory role for zinc dependent protein kinases and cytoskeletal proteins in mediating hypoxic induced constriction of pulmonary endothelial cells.
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Affiliation(s)
- Huihua Li
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
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18
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Varu VN, Ahanchi SS, Hogg ME, Bhikhapurwala HA, Chen A, Popowich DA, Vavra AK, Martinez J, Jiang Q, Saavedra JE, Hrabie JA, Keefer LK, Kibbe MR. Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes. Am J Physiol Heart Circ Physiol 2010; 299:H772-9. [PMID: 20562340 PMCID: PMC2944486 DOI: 10.1152/ajpheart.01234.2009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 06/17/2010] [Indexed: 11/22/2022]
Abstract
Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration. Vascular smooth muscle cells (VSMC) from lean Zucker (LZ) rats were exposed to the NO donor, DETA/NO, following treatment with different glucose and/or insulin concentrations. DETA/NO inhibited VSMC proliferation in a concentration-dependent manner to a greater extent in VSMC exposed to normal-glucose vs. high-glucose environments, and even more effectively in normal-glucose/high-insulin and high-glucose/high-insulin environments. G(0)/G(1) cell cycle arrest and cell death were not responsible for the enhanced efficacy of NO in these environments. Next, type 1 diabetes was induced in LZ rats with streptozotocin. The rat carotid artery injury model was performed. Type 1 diabetic rats experienced no significant reduction in neointimal hyperplasia following arterial injury and treatment with the NO donor PROLI/NO. However, daily administration of insulin to type 1 diabetic rats restored the efficacy of NO at inhibiting neointimal hyperplasia (60% reduction, P < 0.05). In conclusion, these data demonstrate that NO is ineffective at inhibiting neointimal hyperplasia in an uncontrolled rat model of type 1 diabetes; however, insulin administration restores the efficacy of NO at inhibiting neointimal hyperplasia. Thus insulin may play a role in regulating the downstream beneficial effects of NO in the vasculature.
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MESH Headings
- Analysis of Variance
- Animals
- Aorta/drug effects
- Aorta/metabolism
- Aorta/pathology
- Carotid Arteries/drug effects
- Carotid Arteries/metabolism
- Carotid Arteries/pathology
- Cell Death/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- Drug Interactions
- Flow Cytometry
- Hyperplasia/metabolism
- Hyperplasia/pathology
- Insulin/metabolism
- Insulin/pharmacology
- 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/pharmacology
- Rats
- Tunica Intima/drug effects
- Tunica Intima/metabolism
- Tunica Intima/pathology
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Affiliation(s)
- Vinit N Varu
- Division of Vascular Surgery and Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL 60611, USA
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19
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Popowich DA, Vavra AK, Walsh CP, Bhikhapurwala HA, Rossi NB, Jiang Q, Aalami OO, Kibbe MR. Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis. Am J Physiol Heart Circ Physiol 2010; 298:H2192-200. [PMID: 20382856 PMCID: PMC2886652 DOI: 10.1152/ajpheart.00535.2009] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Accepted: 03/24/2010] [Indexed: 02/04/2023]
Abstract
Nitric oxide (NO) induces vascular smooth muscle cell (VSMC) apoptosis in part through activation of p53. Traditionally, p53 has been thought of as the gatekeeper, determining if a cell should undergo arrest and repair or apoptosis following exposure to DNA-damaging agents, depending on the severity of the damage. However, our laboratory previously demonstrated that NO induces apoptosis to a much greater extent in p53(-/-) compared with p53(+/+) VSMC. Increased reactive oxygen species (ROS) within VSMC has been shown to induce VSMC apoptosis, and recently it was found that the absence of, or lack of, functional p53 leads to increased ROS and oxidative stress within different cell types. This study investigated the differences in intracellular ROS levels between p53(-/-) and p53(+/+) VSMC and examined if these differences were responsible for the increased susceptibility to NO-induced apoptosis observed in p53(-/-) VSMC. We found that p53 actually protects VSMC from NO-induced apoptosis by increasing antioxidant protein expression [i.e., peroxiredoxin-3 (PRx-3)], thereby reducing ROS levels and cellular oxidative stress. We also observed that the NO-induced apoptosis in p53(-/-) VSMC was largely abrogated by pretreatment with catalase. Furthermore, when the antioxidant protein PRx-3 and its specific electron acceptor thioredoxin-2 were silenced within p53(+/+) VSMC with small-interfering RNA, not only did these cells exhibit greater ROS production, but they also exhibited increased NO-induced apoptosis similar to that observed in p53(-/-) VSMC. These findings suggest that ROS mediate NO-induced VSMC apoptosis and that p53 protects VSMC from NO-induced apoptosis by decreasing intracellular ROS. This research demonstrates that p53 has antioxidant functions in stressed cells and also suggests that p53 has antiapoptotic properties.
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Affiliation(s)
- Daniel A Popowich
- Division of Vascular Surgery, Northwestern Univ., 676 N. St. Clair, no. 650, Chicago, IL 60611, USA
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20
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Circu ML, Aw TY. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 2010; 48:749-62. [PMID: 20045723 PMCID: PMC2823977 DOI: 10.1016/j.freeradbiomed.2009.12.022] [Citation(s) in RCA: 2420] [Impact Index Per Article: 161.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Revised: 12/21/2009] [Accepted: 12/27/2009] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) are products of normal metabolism and xenobiotic exposure, and depending on their concentration, ROS can be beneficial or harmful to cells and tissues. At physiological low levels, ROS function as "redox messengers" in intracellular signaling and regulation, whereas excess ROS induce oxidative modification of cellular macromolecules, inhibit protein function, and promote cell death. Additionally, various redox systems, such as the glutathione, thioredoxin, and pyridine nucleotide redox couples, participate in cell signaling and modulation of cell function, including apoptotic cell death. Cell apoptosis is initiated by extracellular and intracellular signals via two main pathways, the death receptor- and the mitochondria-mediated pathways. Various pathologies can result from oxidative stress-induced apoptotic signaling that is consequent to ROS increases and/or antioxidant decreases, disruption of intracellular redox homeostasis, and irreversible oxidative modifications of lipid, protein, or DNA. In this review, we focus on several key aspects of ROS and redox mechanisms in apoptotic signaling and highlight the gaps in knowledge and potential avenues for further investigation. A full understanding of the redox control of apoptotic initiation and execution could underpin the development of therapeutic interventions targeted at oxidative stress-associated disorders.
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Affiliation(s)
- Magdalena L Circu
- Department of Molecular & Cellular Physiology, Louisiana University Health Sciences Center, Shreveport, LA 71130, USA
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21
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Ahanchi SS, Varu VN, Tsihlis ND, Martinez J, Pearce CG, Kapadia MR, Jiang Q, Saavedra JE, Keefer LK, Hrabie JA, Kibbe MR. Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome. Am J Physiol Heart Circ Physiol 2008; 295:H2388-98. [PMID: 18931034 DOI: 10.1152/ajpheart.00185.2008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G0/G1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.
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Affiliation(s)
- Sadaf S Ahanchi
- Division of Vascular Surgery, Institute for BioNanotechnology in Medicine, Northwestern University, 201 E. Huron St., Galter 10-105, Chicago, IL 60611, USA
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22
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Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout B, Bahar I. Computational insights on the competing effects of nitric oxide in regulating apoptosis. PLoS One 2008; 3:e2249. [PMID: 18509469 PMCID: PMC2386238 DOI: 10.1371/journal.pone.0002249] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2007] [Accepted: 03/02/2008] [Indexed: 01/05/2023] Open
Abstract
Despite the establishment of the important role of nitric oxide (NO) on apoptosis, a molecular-level understanding of the origin of its dichotomous pro- and anti-apoptotic effects has been elusive. We propose a new mathematical model for simulating the effects of nitric oxide (NO) on apoptosis. The new model integrates mitochondria-dependent apoptotic pathways with NO-related reactions, to gain insights into the regulatory effect of the reactive NO species N(2)O(3), non-heme iron nitrosyl species (FeL(n)NO), and peroxynitrite (ONOO(-)). The biochemical pathways of apoptosis coupled with NO-related reactions are described by ordinary differential equations using mass-action kinetics. In the absence of NO, the model predicts either cell survival or apoptosis (a bistable behavior) with shifts in the onset time of apoptotic response depending on the strength of extracellular stimuli. Computations demonstrate that the relative concentrations of anti- and pro-apoptotic reactive NO species, and their interplay with glutathione, determine the net anti- or pro-apoptotic effects at long time points. Interestingly, transient effects on apoptosis are also observed in these simulations, the duration of which may reach up to hours, despite the eventual convergence to an anti-apoptotic state. Our computations point to the importance of precise timing of NO production and external stimulation in determining the eventual pro- or anti-apoptotic role of NO.
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Affiliation(s)
- Elife Z. Bagci
- Department of Computational Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Biochemistry and Molecular Genetics, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Yoram Vodovotz
- Department of Surgery, School of Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Timothy R. Billiar
- Department of Surgery, School of Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Bard Ermentrout
- Department of Mathematics, Arts & Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail: (IB); (BE)
| | - Ivet Bahar
- Department of Computational Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail: (IB); (BE)
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23
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Abstract
Atherosclerosis in the form of peripheral arterial disease results in significant morbidity and mortality. Surgical treatment options for peripheral arterial disease include angioplasty with and without stenting, endarterectomy, and bypass grafting. Unfortunately, all of these procedures injure the vascular endothelium, which impairs its ability to produce nitric oxide (NO) and ultimately leads to neointimal hyperplasia and restenosis. To improve on current patency rates after vascular procedures, investigators are engaged in research to improve the bioavailability of NO at the site of vascular injury in an attempt to reduce the risk of thrombosis and restenosis after successful revascularization. This article reviews some of the previous research that has aimed to improve NO bioavailability after vascular procedures whether through systemic or local delivery, as well as to describe some of the NO-releasing products that are currently undergoing study for use in clinical practice.
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Affiliation(s)
- Daniel A Popowich
- Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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24
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Kapadia MR, Chow LW, Tsihlis ND, Ahanchi SS, Eng JW, Murar J, Martinez J, Popowich DA, Jiang Q, Hrabie JA, Saavedra JE, Keefer LK, Hulvat JF, Stupp SI, Kibbe MR. Nitric oxide and nanotechnology: a novel approach to inhibit neointimal hyperplasia. J Vasc Surg 2008; 47:173-82. [PMID: 18178471 PMCID: PMC2268106 DOI: 10.1016/j.jvs.2007.09.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2007] [Revised: 08/30/2007] [Accepted: 09/03/2007] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Nitric oxide (NO) has been shown to inhibit neointimal hyperplasia after arterial interventions in several animal models. To date, however, NO-based therapies have not been used in the clinical arena. Our objective was to combine nanofiber delivery vehicles with NO chemistry to create a novel, more potent NO-releasing therapy that can be used clinically. Thus, the aim of this study was to evaluate the perivascular application of spontaneously self-assembling NO-releasing nanofiber gels. Our hypothesis was that this application would prevent neointimal hyperplasia. METHODS Gels consisted of a peptide amphiphile, heparin, and a diazeniumdiolate NO donor (1-[N-(3-Aminopropyl)-N-(3-ammoniopropyl)]diazen-1-ium-1,2-diolate [DPTA/NO] or disodium 1-[(2-Carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate [PROLI/NO]). Nitric oxide release from the gels was evaluated by the Griess reaction, and scanning electron microscopy confirmed nanofiber formation. Vascular smooth muscle cell (VSMC) proliferation and cell death were assessed in vitro by (3)H-thymidine incorporation and Personal Cell Analysis (PCA) system (Guava Technologies, Hayward, Calif). For the in vivo work, gels were modified by reducing the free-water content. Neointimal hyperplasia after periadventitial gel application was evaluated using the rat carotid artery injury model at 14 days (n = 6 per group). Inflammation and proliferation were examined in vivo with immunofluorescent staining against CD45, ED1, and Ki67 at 3 days (n = 2 per group), and graded by blinded observers. Endothelialization was assessed by Evans blue injection at 7 days (n = 3 per group). RESULTS Both DPTA/NO and PROLI/NO, combined with the peptide amphiphile and heparin, formed nanofiber gels and released NO for 4 days. In vitro, DPTA/NO inhibited VSMC proliferation and induced cell death to a greater extent than PROLI/NO. However, the DPTA/NO nanofiber gel only reduced neointimal hyperplasia by 45% (intima/media [I/M] area ratio, 0.45 +/- 0.07), whereas the PROLI/NO nanofiber gel reduced neointimal hyperplasia by 77% (I/M area ratio, 0.19 +/- 0.03, P < .05) vs control (injury alone I/M area ratio, 0.83 +/- 0.07; P < .05). Both DPTA/NO and PROLI/NO nanofiber gels significantly inhibited proliferation in vivo (1.06 +/- 0.30 and 0.19 +/- 0.11 vs injury alone, 2.02 +/- 0.20, P < .05), yet had minimal effect on apoptosis. Only the PROLI/NO nanofiber gel inhibited inflammation (monocytes and leukocytes). Both NO-releasing nanofiber gels stimulated re-endothelialization. CONCLUSIONS Perivascular application of NO-releasing self-assembling nanofiber gels is an effective and simple therapy to prevent neointimal hyperplasia after arterial injury. Our study demonstrates that the PROLI/NO nanofiber gel most effectively prevented neointimal hyperplasia and resulted in less inflammation than the DPTA/NO nanofiber gel. This therapy has great clinical potential to prevent neointimal hyperplasia after open vascular interventions in patients.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Carotid Arteries/drug effects
- Carotid Arteries/metabolism
- Carotid Arteries/pathology
- Carotid Artery Injuries/drug therapy
- Carotid Artery Injuries/metabolism
- Carotid Artery Injuries/pathology
- Cell Death/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Delayed-Action Preparations
- Disease Models, Animal
- Drug Carriers
- Drug Compounding
- Endothelium, Vascular/drug effects
- Gels
- Hyperplasia
- Male
- Models, Molecular
- Molecular Structure
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Nanotechnology/methods
- Nitric Oxide/metabolism
- Nitric Oxide Donors/chemistry
- Nitric Oxide Donors/metabolism
- Nitric Oxide Donors/pharmacology
- Nitric Oxide Donors/therapeutic use
- Proline/analogs & derivatives
- Proline/pharmacology
- Rats
- Rats, Sprague-Dawley
- Time Factors
- Tunica Intima/drug effects
- Tunica Intima/metabolism
- Tunica Intima/pathology
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Affiliation(s)
- Muneera R Kapadia
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Lesley W Chow
- Department of Material Science and Engineering, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Nick D Tsihlis
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Sadaf S Ahanchi
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Jason W Eng
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Jozef Murar
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Janet Martinez
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Daniel A Popowich
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Qun Jiang
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Joseph A Hrabie
- Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Building 538, Frederick, MD
| | - Joseph E Saavedra
- Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Building 538, Frederick, MD
| | - Larry K Keefer
- Laboratory for Comparative Carcinogenesis/Center for Cancer Research, National Cancer Institute-Frederick, Building 538, Frederick, MD
| | - James F Hulvat
- Department of Material Science and Engineering, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Samuel I Stupp
- Department of Material Science and Engineering, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
| | - Melina R Kibbe
- Division of Vascular Surgery, Northwestern University, Chicago, IL
- Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL
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25
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Matsuda N, Hattori Y. Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction. J Smooth Muscle Res 2007; 43:117-37. [PMID: 17928746 DOI: 10.1540/jsmr.43.117] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Sepsis is the leading cause of mortality in critically ill patients. In this pathological syndrome, septic shock and sequential multiple organ failure correlate with poor outcome. The pathophysiology of sepsis with acute organ dysfunction involves a highly complex, integrated response that includes activation of number of cell types, inflammatory mediators, and the hemostatic system. Central to this process may be alterations in vascular functions. This review article provides a growing body of evidence for the potential impact of vascular dysfunction on sepsis pathophysiology with a major emphasis on the endothelium. Furthermore, the role of apoptotic signaling molecules in the mechanisms underlying endothelial cell injury and death during sepsis and its potential value as a target for sepsis therapy will be discussed, which may help in the assessment of ongoing therapeutic strategies.
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Affiliation(s)
- Naoyuki Matsuda
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyoma, Japan
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26
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Jańczyk A, Garcia-Lopez MA, Fernandez-Peñas P, Alonso-Lebrero JL, Benedicto I, López-Cabrera M, Gonzalez S. A Polypodium leucotomos extract inhibits solar-simulated radiation-induced TNF-alpha and iNOS expression, transcriptional activation and apoptosis. Exp Dermatol 2007; 16:823-9. [PMID: 17845214 DOI: 10.1111/j.1600-0625.2007.00603.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In this report, we have examined the molecular basis of the photoprotective effect of a hydrophilic extract of the fern Polypodium leucotomos (PL) in vitro, using a solar simulator as the source of UV radiation (SSR). We found that pretreatment of human keratinocytes with PL inhibited SSR-mediated increase of tumor necrosis factor (TNF)-alpha and also abrogated nitric oxide (NO) production. Consistent with this, PL blocked the induction of inducible nitric oxide synthase (iNOS) elicited by SSR. In addition, PL inhibited the SSR-mediated transcriptional activation of NF-kappaB and AP1. Finally, we demonstrated that pretreatment with PL exerted a cytoprotective effect against SSR-induced damage, resulting in increased cell survival. Together, these data postulate a multifactor mechanism of protection not exclusively reliant on the antioxidant capability of PL, and strengthen the basic knowledge on the photoprotective effect of this botanical agent.
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Affiliation(s)
- Agnieska Jańczyk
- Department of Molecular Biology, Hospital de la Princesa, Madrid, Spain
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27
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Ahanchi SS, Tsihlis ND, Kibbe MR. The role of nitric oxide in the pathophysiology of intimal hyperplasia. J Vasc Surg 2007; 45 Suppl A:A64-73. [PMID: 17544026 DOI: 10.1016/j.jvs.2007.02.027] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2007] [Accepted: 02/11/2007] [Indexed: 12/19/2022]
Abstract
Since its discovery, nitric oxide (NO) has emerged as a biologically important molecule and was even named Molecule of the Year by Science magazine in 1992. Specific to our interests, NO has been implicated in the regulation of vascular pathology. This review begins with a summary of the molecular biology of NO, from its discovery to the mechanisms of endogenous production. Next, we turn our attention to describing the arterial injury response of neointimal hyperplasia, and we review the role of NO in the pathophysiology of neointimal hyperplasia. Finally, we review the literature regarding NO-based therapies. This includes the development of inhalational-based NO therapies, systemically administered L-arginine and NO donors, NO synthase gene therapy, locally applied NO donors, and NO-releasing prosthetic materials. By reviewing the current literature, we emphasize the tremendous clinical potential that NO-based therapies can have on the development of neointimal hyperplasia.
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Affiliation(s)
- Sadaf S Ahanchi
- Division of Vascular Surgery, Northwestern University, Chicago, IL 60611, USA
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28
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Abstract
This article briefly reviews the background of endothelium-dependent vasorelaxation, describes the nitric oxide/cGMP/protein kinase pathway and its role in modulating pulmonary vascular tone and remodeling, and describes three approaches that target the nitric oxide/cGMP pathway in the treatment of patients with pulmonary arterial hypertension.
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Affiliation(s)
- James R Klinger
- Division of Pulmonary Sleep and Critical Care Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
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29
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Zardi EM, Zardi DM, Dobrina A, Afeltra A. Prostacyclin in sepsis: A systematic review. Prostaglandins Other Lipid Mediat 2007; 83:1-24. [PMID: 17259068 DOI: 10.1016/j.prostaglandins.2006.12.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2006] [Revised: 10/24/2006] [Accepted: 12/15/2006] [Indexed: 01/22/2023]
Abstract
According to current literature, infective processes greatly modify both vascular hemodynamics and anti-oxidant properties of affected tissues, causing a change in homeostasis that regulates the correct functioning of all cells responsible for the physiological and metabolic balance of various organs. As a consequence, the response to the infection that has caused the change is also likely to be weaker and, in the case of septic shock, ineffective. In this review, we will take into consideration these mechanisms and then focus on a group of vasodilator drugs (prostacyclin and its analogs) which, though have been used for over 20 years mainly to treat obstructive vascular diseases, have such hemodynamic and anti-inflammatory properties which prevent homeostatic changes. It is obvious that prostacyclin does not definitively have anti-infective characteristics; however, in association with anti-infective drugs (antibiotics, etc.), the effectiveness of the latter appears improved, at least in some circumstances. Similarly, the fact that prostacyclin and its analogs have a cytoprotective effect on the liver and reduce the ischemia-reperfusion damage following liver transplant is not a novelty and evidence that they improve hepatic hemodynamics suggests their use in those pathologies characterized by possible reduced perfusion or ascertained ischemia of the liver.
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Affiliation(s)
- E M Zardi
- Area of Internal Medicine and Immunology, University Campus Bio-Medico, Rome, Italy.
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30
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Curran JN, Winter DC, Bouchier-Hayes D. Biological fate and clinical implications of arginine metabolism in tissue healing. Wound Repair Regen 2007; 14:376-86. [PMID: 16939563 DOI: 10.1111/j.1743-6109.2006.00151.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Since its discovery in 1987, many biological roles (including wound healing) have been identified for nitric oxide (NO). The gas is produced by NO synthase using the dibasic amino acid L-arginine as a substrate. It has been established that a lack of dietary L-arginine delays experimental wound healing. Arginine can also be metabolized to urea and ornithine by arginase-1, a pathway that generates L-proline, a substrate for collagen synthesis, and polyamines, which stimulate cellular proliferation. Herein, we review subjects of interest in arginine metabolism, with emphasis on the biochemistry of wound NO production, relative NO synthase isoform activity in healing wounds, cellular contributions to NO production, and NO effects and mechanisms of action in wound healing.
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Affiliation(s)
- John N Curran
- Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
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31
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Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, Choi AMK. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 2007; 9:49-89. [PMID: 17115887 DOI: 10.1089/ars.2007.9.49] [Citation(s) in RCA: 904] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-kappaB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.
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Affiliation(s)
- Stefan W Ryter
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
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Cooney R, Hynes SO, Duffy AM, Sharif F, O'Brien T. Adenoviral-mediated gene transfer of nitric oxide synthase isoforms and vascular cell proliferation. J Vasc Res 2006; 43:462-72. [PMID: 16921253 DOI: 10.1159/000095163] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2005] [Accepted: 06/06/2006] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Many vascular diseases are associated with reduced nitric oxide (NO) bioavailability. Nitric oxide synthase (NOS) gene therapy to the vasculature is a possible treatment for vascular disease as a means of increasing NO bioavailability, and this may be achieved using any of the NOS isoforms. The aim of our study was to compare the effects of adenoviral-mediated overexpression of the most commonly used NOS isoforms eNOS and iNOS on vascular cell proliferation. METHODS Human coronary artery smooth muscle cells (HCSMCs) and human umbilical vein endothelial cells (HUVECs) were transduced with adenoviral vectors encoding eNOS or iNOS at a multiplicity of infection of 100. Control cells were exposed to AdNull (empty vector) or diluent alone. Transgene expression was sought by Western blotting. The Greiss assay was used to measure nitrite levels. Cell proliferation was assessed by cell counting on days 0, 3 and 6. Apoptosis was sought using FACS analysis. Angiogenesis was measured using a commercially available in vitro kit. RESULTS Expression of both isoforms was detected in transduced cells by Western blot at all three time points. NOS transduction resulted in increased nitrite levels with higher levels seen in iNOS- compared to eNOS-transduced cells. Cell proliferation was diminished in AdeNOS- and AdiNOS-transduced cells compared with non-transduced cells on days 3 and 6 in both HCSMCs and HUVECs. Apoptosis was not detected in either cell line with either of the isoforms at any timepoint studied. Both eNOS and iNOS gene transfer caused a reduction in angiogenesis. CONCLUSIONS NOS gene transfer to both endothelial and vascular smooth muscle cells is antiproliferative and antiangiogenic. The biological effect is identical with both isoforms and there is no evidence to support a differential effect on endothelial and vascular smooth muscle cell biology.
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Affiliation(s)
- Ronan Cooney
- Regenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Sciences (NCBES), National University of Ireland, Galway, Ireland.
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33
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Abstract
Understanding wound healing today involves much more than simply stating that there are three phases: inflammation, proliferation, and maturation. Wound healing is a complex series of reactions and interactions among cells and "mediators." Each year, new mediators are discovered and our understanding of inflammatory mediators and cellular interactions grows. This article will attempt to provide a concise overview on wound healing and wound management.
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Affiliation(s)
- George Broughton
- Department of Plastic Surgery, Nancy L & Perry Bass Advanced Wound Healing Laboratory, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9132, USA.
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34
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Chen X, Niroomand F, Liu Z, Zankl A, Katus HA, Jahn L, Tiefenbacher CP. Expression of nitric oxide related enzymes in coronary heart disease. Basic Res Cardiol 2006; 101:346-53. [PMID: 16705470 DOI: 10.1007/s00395-006-0592-5] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2005] [Accepted: 12/22/2005] [Indexed: 11/27/2022]
Abstract
Enzymes involved in the metabolism nitric oxide (NO) and reactive oxygen species (ROS) may play a role for the decreased availability of NO in atherosclerosis. We, therefore, hypothesized that the pattern of gene expression of these enzymes is altered in atherosclerosis. Myocardial tissue from patients with coronary heart disease (CHD) or without CHD (control group) was investigated. The level of enzymes related to NO/ROS metabolism was determined both at mRNA level and protein level by rt-PCR, real-time PCR, and western blot. The expression of NOS1-3 (synthesis of NO), arginase1 (reduction of L-arginine), p22phox (active subunit of NADPH oxidase), GTPCH (rate limiting enzyme for tetrahydrobiopterin), SOD1-3 (scavengers of superoxide anions), PRTMT1-3, and DDAH2 (involved in the metabolism of ADMA) was determined. All enzymes were found to be expressed in human myocardium. NOS isoforms were decreased in CHD in protein level, but only the downregulation of NOS3 expression reached statistical significance. The expression of PRMT1 and PRMT3 was increased. In addition, the expression of DDAH2 was reduced, both theoretically leading to an increase of ADMA concentration. SOD3 was downregulated in tissue from patients with CHD. Taken together, in myocardial tissue from patients with atherosclerosis, the expression of genes increasing ADMA levels is enhanced in contrast to a reduced expression of genes promoting NO synthesis. These results may contribute to the explanation of increased oxidative stress in atherosclerosis on the level of gene expression.
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Affiliation(s)
- X Chen
- Department of Cardiology, University of Heidelberg, INF 410, 69120, Heidelberg, Germany
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35
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St Croix CM, Leelavaninchkul K, Watkins SC, Kagan VE, Pitt BR. Nitric oxide and zinc homeostasis in acute lung injury. Ann Am Thorac Soc 2006; 2:236-42. [PMID: 16222044 PMCID: PMC2713321 DOI: 10.1513/pats.200501-007ac] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Among putative small molecules that affect sensitivity to acute lung injury, zinc and nitric oxide are potentially unique by virtue of their interdependence and dual capacities to be cytoprotective or injurious. Nitric oxide and zinc appear to be linked via an intracellular signaling pathway involving S-nitrosation of metallothoinein--itself a small protein known to be an important inducible gene product that may modify lung injury. In the present article, we summarize recent efforts using genetic and fluorescence optical imaging techniques to: (1) demonstrate that S-nitrosation of metallothionein affects intracellular zinc homeostasis in intact pulmonary endothelial cells; and (2) reveal a protective role for this pathway in hyperoxic and LPS-induced injury.
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Affiliation(s)
- Claudette M St Croix
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School Public Health, Pittsburgh, PA 15260, USA.
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36
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Wu L, Wang R. Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev 2005; 57:585-630. [PMID: 16382109 DOI: 10.1124/pr.57.4.3] [Citation(s) in RCA: 663] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented. A plethora of studies have also shown the importance of the roles of CO in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems. Our understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced. Many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function. Enhancement of endogenous CO production and direct delivery of exogenous CO have found their applications in many health research fields and clinical settings. Future studies will further clarify the gasotransmitter role of CO, provide insight into the pathogenic mechanisms of many CO abnormality-related diseases, and pave the way for innovative preventive and therapeutic strategies based on the physiologic effects of CO.
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Affiliation(s)
- Lingyun Wu
- Department of Biology, Lakehead University, 955 Oliver Rd., Thunder Bay, Ontario, Canada P7B 5E1
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37
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Abstract
Nitrosative stress can prevent or induce apoptosis. It occurs via S-nitrosylation by the interaction of nitric oxide (NO) with the biological thiols of proteins. Cellular redox potential and non-heme iron content determine S-nitrosylation. Apoptotic cell death is inhibited by S-nitrosylation of the redox-sensitive thiol in the catalytic site of caspase family proteases, which play an essential role in the apoptotic signal cascade. Nitrosative stress can also promote apoptosis by the activation of mitochondrial apoptotic pathways, such as the release of cytochrome c, an apoptosis-inducing factor, and endonuclease G from mitochondria, as well as the suppression of NF-kB activity. In this article we reviewed the mechanisms whereby S-nitrosylation and nitrosative stress regulate the apoptotic signal cascade.
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Affiliation(s)
- Ki-Mo Kim
- Vascular System Research Center, Kangwon National University, Chunchon, Kangwon-do, Korea
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38
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Choi BM, Pae HO, Jang SI, Kim YM, Chung HT. Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator. BMB Rep 2005; 35:116-26. [PMID: 16248976 DOI: 10.5483/bmbrep.2002.35.1.116] [Citation(s) in RCA: 157] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Nitric oxide (NO), synthesized from L-arginine by NO synthases, is a small, lipophilic, diffusible, highly reactive molecule with dichotomous regulatory roles in many biological events under physiological and pathological conditions. NO can promote apoptosis (pro-apoptosis) in some cells, whereas it inhibits apoptosis (anti-apoptosis) in other cells. This complexity is a consequence of the rate of NO production and the interaction with biological molecules such as metal ion, thiol, protein tyrosine, and reactive oxygen species. Long-lasting overproduction of NO acts as a pro-apoptotic modulator, activating caspase family proteases through the release of mitochondrial cytochrome c into cytosol, up-regulation of the p53 expression, and alterations in the expression of apoptosis-associated proteins, including the Bcl-2 family. However, low or physiological concentrations of NO prevent cells from apoptosis that is induced by the trophic factor withdrawal, Fas, TNFalpha/ActD, and LPS. The anti-apoptotic mechanism is understood on the basis of gene transcription of protective proteins. These include: heat shock protein, hemeoxygenase, or cyclooxygenase-2 and direct inhibition of the apoptotic executive effectors caspase family protease by S-nitrosylation of the cysteine thiol group in their catalytic site in a cell specific way. Our current understanding of the mechanisms by which NO exerts both pro- and anti-apototic action is discussed in this review article.
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Affiliation(s)
- Byung-Min Choi
- Medicinal Resources Research Center (MRRC), Wonkwang University, Iksan, Chunbug, Korea
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39
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Mangi AA. Gene and Cell‐based Therapies for Cardiovascular Disease. MODERN BIOPHARMACEUTICALS 2005:305-324. [DOI: 10.1002/9783527620982.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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40
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Barbato JE, Zuckerbraun BS, Overhaus M, Raman KG, Tzeng E. Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome. Am J Physiol Heart Circ Physiol 2005; 289:H228-36. [PMID: 15734883 DOI: 10.1152/ajpheart.00982.2004] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.
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Affiliation(s)
- Joel E Barbato
- Dept. of Surgery, Univ. of Pittsburgh, A1010 PUH, 200 Lothrop St., Pittsburgh, PA 15213, USA
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Cakir Y, Ballinger SW. Reactive species-mediated regulation of cell signaling and the cell cycle: the role of MAPK. Antioxid Redox Signal 2005; 7:726-40. [PMID: 15890019 DOI: 10.1089/ars.2005.7.726] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cardiovascular disease development is significantly influenced by the effects of reactive species (RS). By virtue of their controlled production, regulation, and reactive nature, RS play important roles in the modulation of cellular signaling, growth, and death in the vasculature. Concentration gradients are important in determining the effects of RS. Low to moderate concentrations of RS act as mediators in signaling cascades and gene regulation, whereas high levels of RS cause cellular damage and death. Because a dual redox regulation state seems to exist in several signaling cascades, e.g., RS often induce upstream initiating events, whereas downstream events are reliant on reductive processes, alterations in cellular redox states influence the activation/inactivation of signaling events and transcription factors. In this review, the relationships between RS, specific signal transduction pathways, and aspects of cell-cycle control are discussed.
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Affiliation(s)
- Yavuz Cakir
- Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
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42
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Vodovotz Y, Zamora R, Lieber MJ, Luckhart S. Cross-talk between nitric oxide and transforming growth factor-beta1 in malaria. Curr Mol Med 2005; 4:787-97. [PMID: 15579025 PMCID: PMC2590626 DOI: 10.2174/1566524043359999] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Malaria has re-emerged as a global health problem, leading to an increased focus on the cellular and molecular biology of the mosquito Anopheles and the parasite Plasmodium with the goal of identifying novel points of intervention in the parasite life cycle. Anti-parasite defenses mounted by both mammalian hosts and Anopheles can suppress the growth of Plasmodium. Nonetheless, the parasite is able to escape complete elimination in vivo, perhaps by thwarting or co-opting these mechanisms for its own survival, as do numerous other pathogens. Among the defense systems used by the mammalian host against Plasmodium is the synthesis of nitric oxide (NO), catalyzed by an inducible NO synthase (iNOS). Nitric oxide produced by the action of an inducible Anopheles stephensi NO synthase (AsNOS) may be central to the anti-parasitic arsenal of this mosquito. In mammals, iNOS can be modulated by members of the transforming growth factor-beta (TGF-beta) cytokine superfamily. Transforming growth factor-beta is produced as an inactive precursor that is activated following dissociation of certain inhibitory proteins, a process that can be promoted by reaction products of NO as well as by hemin. Ingestion by Anopheles of blood containing Plasmodium initiates parasite development, blood digestion which results in the accumulation of hematin (hemin) in the insect midgut, and induction of both AsNOS and TGF-beta-like (As60A) gene expression in the midgut epithelium. Active mammalian TGF-beta1 can be detected in the A. stephensi midgut up to 48h post-ingestion and latent TGF-beta1 can be activated by midgut components in vitro, a process that is potentiated by NO and that may involve hematin. Further, mammalian TGF-beta1 is perceived as a cytokine by A. stephensi cells in vitro and can alter Plasmodium development in vivo. Bloodfeeding by Anopheles, therefore, results in a juxtaposition of evolutionarily conserved mosquito and mammalian TGF-beta superfamily homologs that may influence transmission dynamics of Plasmodium in endemic regions.
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Affiliation(s)
- Yoram Vodovotz
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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43
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Lee SJ, Kim KM, Namkoong S, Kim CK, Kang YC, Lee H, Ha KS, Han JA, Chung HT, Kwon YG, Kim YM. Nitric Oxide Inhibition of Homocysteine-induced Human Endothelial Cell Apoptosis by Down-regulation of p53-dependent Noxa Expression through the Formation of S-Nitrosohomocysteine. J Biol Chem 2005; 280:5781-8. [PMID: 15561702 DOI: 10.1074/jbc.m411224200] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Hyperhomocysteinemia is believed to induce endothelial dysfunction and promote atherosclerosis; however, the pathogenic mechanism has not been clearly elucidated. In this study, we examined the molecular mechanism by which homocysteine (HCy) causes endothelial cell apoptosis and by which nitric oxide (NO) affects HCy-induced apoptosis. Our data demonstrated that HCy caused caspase-dependent apoptosis in cultured human umbilical vein endothelial cells, as determined by cell viability, nuclear condensation, and caspase-3 activation and activity. These apoptotic characteristics were correlated with reactive oxygen species (ROS) production, lipid peroxidation, p53 and Noxa expression, and mitochondrial cytochrome c release following HCy treatment. HCy also induced p53 and Noxa expression and apoptosis in endothelial cells from wild type mice but not in the p53-deficient cells. The NO donor S-nitroso-N-acetylpenicillamine, adenoviral transfer of inducible NO synthase gene, and antioxidants (alpha-tocopherol and superoxide dismutase plus catalase) but not oxidized SNAP, 8-Br-cGMP, nitrite, and nitrate, suppressed ROS production, p53-dependent Noxa expression, and apoptosis induced by HCy. The cytotoxic effect of HCy was decreased by small interfering RNA-mediated suppression of Noxa expression, indicating that Noxa up-regulation plays an important role in HCy-induced endothelial cell apoptosis. Overexpression of inducible NO synthase increased the formation of S-nitroso-HCy, which was inhibited by the NO synthase inhibitor N-monomethyl-l-arginine. Moreover, S-nitroso-HCy did not increase ROS generation, p53-dependent Noxa expression, and apoptosis. These results suggest that up-regulation of p53-dependent Noxa expression may play an important role in the pathogenesis of atherosclerosis induced by HCy and that an increase in vascular NO production may prevent HCy-induced endothelial dysfunction by S-nitrosylation.
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Affiliation(s)
- Seon-Jin Lee
- Vascular System Research Center and Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, Kangwon-do 200-701, Korea
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Monteiro HP, Silva EF, Stern A. Nitric oxide: a potential inducer of adhesion-related apoptosis--anoikis. Nitric Oxide 2005; 10:1-10. [PMID: 15050529 DOI: 10.1016/j.niox.2004.02.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2003] [Revised: 12/29/2003] [Indexed: 12/15/2022]
Abstract
Among the many initiating events that lead to apoptosis or programmed cell death, loss of contact between the cell and the extracellular matrix has been extensively studied. Adhesion-related apoptosis referred to as anoikis is initiated by the action of anti-adhesive substances. Nitric oxide is one of these anti-adhesive substances that have the capacity to signal and trigger pro-apoptotic events in a variety of cell types. Nitric oxide can inhibit cell adhesion, interfere with the assembly of focal adhesion complexes, and disrupt the cell-extracellular matrix interactions. These actions occur in cell that exhibit a dissociation of growth factor signals from alterations in the cytoskeleton, ultimately leading to apoptosis. Since this involves anti-adhesive events, nitric oxide can be considered as causing anoikis. This review article summarizes the available evidence of how nitric oxide participates in apoptosis induced by loss of anchorage (anoikis).
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Affiliation(s)
- H P Monteiro
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
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Abstract
Vascular bypass surgery involves the use of a vascular conduit to circumvent a site of vascular compromise. Vascular graft failure continues to plague both the patients receiving and the surgeons performing these interventions. Demand for the development of a therapy to reduce intimal hyperplasia--the most common cause of bypass graft failure--is significant and has been the goal of many biotechnology groups. The development of gene therapy as a feasible clinical intervention has allowed for novel methods of inhibiting intimal hyperplasia to be conceived. This review describes the evolution of gene transfer of the inducible nitric oxide synthase (iNOS) gene, one of the most successful preclinical interventions to date for vascular disease.
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Affiliation(s)
- Joel E Barbato
- Department of Surgery, University of Pittsburgh, 200 Lothrop, Pittsburgh, PA 15213, USA
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Kasper HU, Wolf H, Drebber U, Wolf HK, Kern MA. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma: Correlation with microvessel density. World J Gastroenterol 2004; 10:1918-22. [PMID: 15222037 PMCID: PMC4572231 DOI: 10.3748/wjg.v10.i13.1918] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas.
METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data.
RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density. However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data.
CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2 expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.
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Affiliation(s)
- Hans-U Kasper
- Department of Pathology, University of Cologne, Joseph-Stelzmann-Strasse 9, D-50931 Koeln, Germany.
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Thomas S, Balasubramanian KA. Role of intestine in postsurgical complications: involvement of free radicals. Free Radic Biol Med 2004; 36:745-56. [PMID: 14990353 DOI: 10.1016/j.freeradbiomed.2003.11.027] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2003] [Revised: 11/10/2003] [Accepted: 11/14/2003] [Indexed: 12/14/2022]
Abstract
Surgery at any location in the body leads to surgical stress response and alterations in normal body homeostasis. The intestine is extremely sensitive to surgical stress even at remote locations and the gastrointestinal tract plays an important role in the development of postsurgical complications such as sepsis, the systemic immune response syndrome (SIRS), and multiple organ failure syndrome (MOFS). The generation of free radicals and subsequent biochemical alterations at the cellular and subcellular level in the intestine has been suggested to play an important role in this process. These oxidative stress-induced events in the mucosa might act as an initiator of distant organ damage and also facilitate bacterial adherence onto the epithelium and translocation into the systemic circulation. This review attempts to highlight the important role of intestine and oxygen free radicals in initiating post-surgical complications.
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Affiliation(s)
- Simmy Thomas
- The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore 632004, India
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48
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Reinehr R, Görg B, Höngen A, Häussinger D. CD95-tyrosine Nitration Inhibits Hyperosmotic and CD95 Ligand-induced CD95 Activation in Rat Hepatocytes. J Biol Chem 2004; 279:10364-73. [PMID: 14679192 DOI: 10.1074/jbc.m311997200] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Epidermal growth factor receptor-dependent CD95-tyrosine phosphorylation was recently identified as an early step in apoptosis induction via the CD95 system (Reinehr, R., Schliess, F., and Häussinger, D. (2003) FASEB J. 17, 731-733). The effect of peroxynitrite (ONOO(-)) on modulation of the hyperosmotic and CD95 ligand (CD95L)-induced CD95 activation process was studied. Pretreatment of hepatocytes with ONOO(-) inhibited CD95L- and hyperosmolarity-induced CD95 membrane trafficking and formation of the death-inducing signaling complex, but not epidermal growth factor receptor activation and its association with CD95. Under these conditions, however, no tyrosine phosphorylation of CD95 occurred; instead, CD95 was tyrosine-nitrated. When ONOO(-) was added after induction of CD95-tyrosine phosphorylation by CD95L or hyperosmolarity, tyrosine nitration of CD95 was largely prevented and death-inducing signaling complex formation occurred. CD95-tyrosine nitration abolished the hyperosmotic sensitization of hepatocytes toward CD95L-induced apoptosis. Additionally, in CD95-yellow fluorescent protein-transfected Huh7-hepatoma cells, ONOO(-) induced CD95 Tyr nitration and prevented CD95L-induced Tyr phosphorylation and apoptosis. Tyrosine-nitrated CD95 was also found in rat livers derived from an in vivo model of endotoxinemia. The data suggest that CD95-tyrosine nitration prevents CD95 activation by inhibiting CD95-tyrosine phosphorylation. Apparently, CD95-tyrosine phosphorylation and nitration are mutually exclusive. The data identify critical tyrosine residues of CD95 as another target of the anti-apoptotic action of NO.
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Affiliation(s)
- Roland Reinehr
- Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, Germany
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Sylte MJ, Inzana TJ, Czuprynski CJ. Reactive oxygen and nitrogen intermediates contribute to Haemophilus somnus lipooligosaccharide-mediated apoptosis of bovine endothelial cells. Vet Immunol Immunopathol 2004; 97:207-17. [PMID: 14741139 DOI: 10.1016/j.vetimm.2003.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Although Haemophilus somnus causes septicemia and vasculitis in cattle, relatively little is known about how H. somnus affects endothelial cells in vitro. We previously reported that H. somnus lipooligosaccharide (LOS)-induced activation of caspases-3, -8 and -9, and apoptosis of bovine pulmonary artery endothelial cells (BPAEC) in vitro. Previous reports indicate that the generation of reactive oxygen species (ROS) or reactive nitrogen intermediates (RNI) can contribute to the induction of apoptosis. In the present study, we sought to determine whether ROS and RNI are involved in LOS-mediated apoptosis of BPAEC. We found that H. somnus LOS induced the generation of ROS in BPAEC, which was blocked by pretreatment with membrane permeable ROS scavengers, such as dimethylsulfoxide (DMSO) and allopurinol (AP). Addition of DMSO or AP significantly reduced H. somnus LOS-mediated caspase-3 activation. Addition of membrane impermeable ROS scavengers (e.g. catalase and superoxide dismutase), failed to block LOS-mediated caspase-3 activation, suggesting a role for intracellular generation of ROS in LOS-induced apoptosis of BPAEC. Addition of N(G)-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, which are selective inhibitors of nitric oxide synthase, blocked NO release and significantly reduced caspase-3 activation in LOS treated BPAEC. These data suggest H. somnus LOS triggers endogenous ROS and RNI production by endothelial cells, which contributes to apoptosis.
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Affiliation(s)
- Matt J Sylte
- Department of Pathobiological Sciences, School of Veterinary Medicine, 2015 Linden Drive West, Madison, WI 53706, USA
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50
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Gage FA, Vodovotz Y. Normalization of nitric oxide flux improves physiological parameters of porcine kidneys maintained on pulsatile perfusion. Nitric Oxide 2003; 9:141-7. [PMID: 14732337 DOI: 10.1016/j.niox.2003.10.001] [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: 10/26/2022]
Abstract
Early endothelial damage and resultant reduction in the beneficial production of nitric oxide (NO) derived from the endothelial NO synthase (eNOS) are phenomena associated with the functional degradation of transplanted kidneys. In contrast, the inflammation characteristic of kidney preservation leads to the later, detrimental expression of the inducible NO synthase (iNOS). We reasoned that provision of low-level NO (to compensate for lack of eNOS) using the chemical NO donor S-nitrosoglutathione (GSNO), along with an iNOS inhibitor (N-omega iminoethyl-L-lysine; L-NIL), might "normalize" NO levels and therefore be beneficial in maintenance of flow. Non-heartbeating donor porcine kidneys were subjected to 30-45 min warm ischemic time and stored from 3 to 30 h, simulating the time required for national sharing. The kidneys were then machine preserved with Belzer MPS (BMP) at a set systolic pressure of 40 mmHg. Eight kidneys were perfused for 5h with BMP only (Group 1 control), 8 kidneys with BMP+GSNO only (Group 2), and 8 kidneys with BMP+GSNO+L-NIL (Group 3). Lower vascular resistance (VR) is a predictor of improved end-organ function. Both Group 2 and 3 kidneys demonstrated statistically significant reduction in VR as compared to Group 1 kidneys, with Group 3 kidneys demonstrating a greater drop in VR than Group 2. Reduced oxygen saturation suggests a higher metabolic rate. Only Group 3 had lower oxygen saturation as compared to Group 1. Increased Ca2+ concentration in the perfusate is a predictor of worse end-organ function. Group 2, but not Group 3, had a higher perfusate Ca2+ concentration than Group 1. The combination of suppression of harmful amounts of NO, while supplying a constant low-level amount of NO, may improve pulsatile kidney preservation.
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