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Ferric C Fang - One of the best experts on this subject based on the ideXlab platform.
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manganese import protects salmonella enterica serovar typhimurium against Nitrosative Stress
Metallomics, 2020Co-Authors: Shehla Yousuf, Joyce E Karlinsey, Stephanie L Neville, Christopher A Mcdevitt, Stephen J Libby, Ferric C Fang, Elaine R FrawleyAbstract:Nitric oxide (NO˙) is a radical molecule produced by mammalian phagocytic cells as part of the innate immune response to bacterial pathogens. It exerts its antimicrobial activity in part by impairing the function of metalloproteins, particularly those containing iron and zinc cofactors. The pathogenic Gram-negative bacterium Salmonella enterica serovar typhimurium undergoes dynamic changes in its cellular content of the four most common metal cofactors following exposure to NO˙ Stress. Zinc, iron and magnesium all decrease in response to NO˙ while cellular manganese increases significantly. Manganese acquisition is driven primarily by increased expression of the mntH and sitABCD transporters following derepression of MntR and Fur. ZupT also contributes to manganese acquisition in response to Nitrosative Stress. S. Typhimurium mutants lacking manganese importers are more sensitive to NO˙, indicating that manganese is important for resistance to Nitrosative Stress.
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the staphylococcus aureus srrab two component system promotes resistance to Nitrosative Stress and hypoxia
Mbio, 2013Co-Authors: Traci L Kinkel, Paul M Dunman, Christelle M Roux, Ferric C FangAbstract:Staphylococcus aureus is both a commensal and a pathogen of the human host. Survival in the host environment requires resistance to host-derived nitric oxide (NO·). However, S. aureus lacks the NO·-sensing transcriptional regulator NsrR that is used by many bacteria to sense and respond to NO·. In this study, we show that S. aureus is able to sense and respond to both NO· and hypoxia by means of the SrrAB two-component system (TCS). Analysis of the S. aureus transcriptome during Nitrosative Stress demonstrates the expression of SrrAB-dependent genes required for cytochrome biosynthesis and assembly (qoxABCD, cydAB, hemABCX), anaerobic metabolism (pflAB, adhE, nrdDG), iron-sulfur cluster repair (scdA), and NO· detoxification (hmp). Targeted mutations in SrrAB-regulated loci show that hmp and qoxABCD are required for NO· resistance, whereas nrdDG is specifically required for anaerobic growth. We also show that SrrAB is required for survival in static biofilms, most likely due to oxygen limitation. Activation by hypoxia, NO·, or a qoxABCD quinol oxidase mutation suggests that the SrrAB TCS senses impaired electron flow in the electron transport chain rather than directly interacting with NO· in the manner of NsrR. Nevertheless, like NsrR, SrrAB achieves the physiological goals of selectively expressing hmp in the presence of NO· and minimizing the potential for Fenton chemistry. Activation of the SrrAB regulon allows S. aureus to maintain energy production and essential biosynthetic processes, repair damage, and detoxify NO· in diverse host environments. Importance The Hmp flavohemoglobin is required for nitric oxide resistance and is widely distributed in bacteria. Hmp expression must be tightly regulated, because expression under aerobic conditions in the absence of nitric oxide can exacerbate oxidative Stress. In most organisms, hmp expression is controlled by the Fe-S cluster-containing repressor NsrR, but this transcriptional regulator is absent in the human pathogen Staphylococcus aureus. We show here that S. aureus achieves hmp regulation in response to nitric oxide and oxygen limitation by placing it under the control of the SrrAB two-component system, which senses reduced electron flow through the respiratory chain. This provides a striking example of convergent evolution, in which the common physiological goals of responding to Nitrosative Stress while minimizing Fenton chemistry are achieved by distinct regulatory mechanisms.
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the nsrr regulon in Nitrosative Stress resistance of salmonella enterica serovar typhimurium
Molecular Microbiology, 2012Co-Authors: Joyce E Karlinsey, Elaine R Frawley, Iel Soo Bang, Lynne A Becker, Steffen Porwollik, Hannah Robbins, Vinai Chittezham Thomas, Rodolfo Urbano, Michael Mcclelland, Ferric C FangAbstract:Nitric oxide (NO·) is an important mediator of innate immunity. The facultative intracellular pathogen Salmonella has evolved mechanisms to detoxify and evade the antimicrobial actions of host-derived NO· produced during infection. Expression of the NO·-detoxifying flavohaemoglobin Hmp is controlled by the NO·-sensing transcriptional repressor NsrR and is required for Salmonella virulence. In this study we show that NsrR responds to very low NO· concentrations, suggesting that it plays a primary role in the Nitrosative Stress response. Additionally, we have defined the NsrR regulon in Salmonella enterica sv. Typhimurium 14028s using transcriptional microarray, qRT-PCR and in silico methods. A novel NsrR-regulated gene designated STM1808 has been identified, along with hmp, hcp-hcr, yeaR-yoaG, ygbA and ytfE. STM1808 and ygbA are important for S. Typhimurium growth during Nitrosative Stress, and the hcp-hcr locus plays a supportive role in NO· detoxification. ICP-MS analysis of purified STM1808 suggests that it is a zinc metalloprotein, with histidine residues H32 and H82 required for NO· resistance and zinc binding. Moreover, STM1808 and ytfE promote Salmonella growth during systemic infection of mice. Collectively, these findings demonstrate that NsrR-regulated genes in addition to hmp are important for NO· detoxification, Nitrosative Stress resistance and Salmonella virulence.
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the Nitrosative Stress response of staphylococcus aureus is required for resistance to innate immunity
Molecular Microbiology, 2006Co-Authors: Anthony R Richardson, Paul M Dunman, Ferric C FangAbstract:Staphylococcus aureus is a highly virulent human pathogen with an extensive array of strategies to subvert the innate immune response. An important aspect of innate immunity is the production of the nitrogen monoxide radical (Nitric Oxide, NO.). Here we describe an adaptive response to Nitrosative Stress that allows S. aureus to replicate at high concentrations of NO.. Microarray analysis revealed 84 staphylococcal genes with significantly altered expression following NO. exposure. Of these, 30 are involved with iron-homeostasis, potentially under the control of the Fur regulator. Another seven induced genes are involved in hypoxic/fermentative metabolism, including the flavohaemoprotein, Hmp. The SrrAB two-component system has been shown to regulate the expression of many of the NO.-induced metabolic genes. Indeed, inactivation of hmp, srrAB and fur resulted in heightened NO. sensitivity. Hmp was responsible for c. 90% of measurable staphylococcal NO. consumption and therefore critical for efficient NO. detoxification. While SrrAB was required for maximal hmp expression, srrAB mutants still exhibited significant NO. scavenging and NO.-dependent induction of hmp. Yet S. aureus lacking SrrAB were more sensitive to Nitrosative Stress than hmp mutants, indicating that the contribution of SrrAB to NO. resistance extends beyond the regulation of hmp expression. Both Hmp and SrrAB were required for full virulence in a murine sepsis model, however, only the attenuation of the hmp mutant was restored by the abrogation of host NO. production. Thus, the S. aureus Hmp protein has evolved to serve as an iNOS-dependent virulence determinant.
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inhibition of bacterial dna replication by zinc mobilization during Nitrosative Stress
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Jeffrey M Schapiro, Stephen J Libby, Ferric C FangAbstract:Abstract Phagocytic cells inhibit the growth of intracellular pathogens by producing nitric oxide (NO). NO causes cell filamentation, induction of the SOS response, and DNA replication arrest in the Gram-negative bacterium Salmonella enterica. NO also induces double-stranded chromosomal breaks in replication-arrested Salmonella lacking a functional RecBCD exonuclease. This DNA damage depends on actions of additional DNA repair proteins, the RecG helicase, and RuvC endonuclease. Introduction of a recG mutation restores both resistance to NO and the ability of an attenuated recBC mutant Salmonella strain to cause lethal infection in mice, demonstrating that bacterial DNA replication is inhibited during host–pathogen interactions. Inhibition of DNA replication during Nitrosative Stress is invariably accompanied by zinc mobilization, implicating DNA-binding zinc metalloproteins as critical targets of NO-related antimicrobial activity.
Shukmei Ho - One of the best experts on this subject based on the ideXlab platform.
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sex hormones induce direct epithelial and inflammation mediated oxidative Nitrosative Stress that favors prostatic carcinogenesis in the noble rat
American Journal of Pathology, 2007Co-Authors: Irwin Leav, Shukmei HoAbstract:Oxidative and Nitrosative Stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administration of testosterone plus 17β-estradiol to Noble rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2′-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/Nitrosative Stress in epithelium. We concluded that the oxidative/Nitrosative damage resulting from the testosterone-plus-17β-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alterations in the hormonal milieu with oxidative/Nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.
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Sex hormones induce direct epithelial and inflammation-mediated oxidative/Nitrosative Stress that favors prostatic carcinogenesis in the noble rat.
American Journal of Pathology, 2007Co-Authors: Irwin Leav, Shukmei HoAbstract:Oxidative and Nitrosative Stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administration of testosterone plus 17β-estradiol to Noble rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2′-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/Nitrosative Stress in epithelium. We concluded that the oxidative/Nitrosative damage resulting from the testosterone-plus-17β-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alterations in the hormonal milieu with oxidative/Nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.
Jonathan S Stamler - One of the best experts on this subject based on the ideXlab platform.
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a genetic analysis of Nitrosative Stress
Biochemistry, 2009Co-Authors: Matthew W Foster, Limin Liu, Ming Zeng, Douglas T Hess, Jonathan S StamlerAbstract:Nitrosative Stress is induced by pathophysiological levels of nitric oxide (NO) and S-nitrosothiols (e.g., S-nitrosoglutathione, GSNO) and arises, at least in significant part, from the nitrosylati...
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enzymes that counteract Nitrosative Stress promote fungal virulence
Current Biology, 2003Co-Authors: Marisol De Jesusberrios, Limin Liu, Jonathan S Stamler, Jesse C Nussbaum, Gary M Cox, Joseph HeitmanAbstract:Abstract Enzymes that protect cells from reactive oxygen species (superoxide dismutase, catalase, peroxidase) have well-established roles in mammalian biology and microbial pathogenesis. Two recently identified enzymes detoxify nitric oxide (NO)-related molecules; flavohemoglobin denitrosylase consumes NO, and S-nitrosoglutathione (GSNO) reductase metabolizes GSNO [1–6]. Although both enzymes protect microorganisms from Nitrosative challenge in vitro, their relevance has not been established in physiological contexts. Here we studied their biological functions in Cryptococcus neoformans, an established human fungal pathogen that replicates in macrophages and whose growth in vitro and in infected animals is controlled by NO bioactivity [7–11]. We show that both flavohemoglobin denitrosylase and GSNO reductase contribute to C. neoformans pathogenesis. FHB1 and GNO1 mutations abolished NO- and GSNO-consuming activity, respectively. Growth of fhb1 mutant cells was inhibited by Nitrosative challenge, whereas that of gno1 mutants was not. fhb1 mutants showed attenuated virulence in a murine model, and virulence was restored in iNOS −/− animals. Survival of the fhb1 mutant was also reduced in activated macrophages and restored to wild-type by inhibition of NOS activity. Combining mutations in flavohemoglobin and GSNO reductase, or flavohemoglobin and superoxide dismutase, further attenuated virulence. These studies illustrate that fungal pathogens elaborate enzymatic defenses against Nitrosative Stress mounted by the host.
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protection from Nitrosative Stress by yeast flavohemoglobin
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Limin Liu, Ming Zeng, Alfred Hausladen, Joseph Heitman, Jonathan S StamlerAbstract:Yeast hemoglobin was discovered close to half a century ago, but its function has remained unknown. Herein, we report that this flavohemoglobin protects Saccharomyces cerevisiae from Nitrosative Stress. Deletion of the flavohemoglobin gene (YHB1) abolished the nitric oxide (NO)-consuming activity of yeast cells. Levels of protein nitrosylation were more than 10-fold higher in yhb1 mutant yeast than in isogenic wild-type cells after incubation with NO donors. Growth of mutant cells was inhibited by a Nitrosative challenge that had little effect on wild-type cells, whereas the resistance of mutant cells to oxidative Stress was unimpaired. Protection conferred by yeast flavohemoglobin against NO and S-nitrosothiols was seen under both anaerobic and aerobic conditions, consistent with a primary function in NO detoxification. A phylogenetic analysis indicated that protection from Nitrosative Stress is likely to be a conserved function among microorganismal flavohemoglobins. Flavohemoglobin is therefore a potential target for antimicrobial therapy.
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Nitrosative Stress activation of the transcription factor oxyr
Cell, 1996Co-Authors: Alfred Hausladen, Christopher T Privalle, Teresa Keng, Joseph Deangelo, Jonathan S StamlerAbstract:Abstract Hydrogen peroxide (H 2 O 2 ) imposes an oxidative Stress to Escherichia coli that is manifested by oxidation of glutathione and related redox-sensitive targets. OxyR is a thiol-containing transcriptional activator whose oxidation controls the expression of genes involved in H 2 O 2 detoxification. Here we report that certain S-nitrosothiols (RSNOs) impose what we term a "Nitrosative Stress" to E. coli, evidenced by lowering of intracellular thiol and the transcriptional activation of OxyR by S-nitrosylation. This cellular and genetic response determines the metabolic fate of RSNOs and thereby contributes to bacterial rescue from stasis. Our studies reveal that signaling by S-nitrosylation can extend to the level of transcription and describe a metabolic pathway that constitutes an adaptation to Nitrosative Stress.
Elaine R Frawley - One of the best experts on this subject based on the ideXlab platform.
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manganese import protects salmonella enterica serovar typhimurium against Nitrosative Stress
Metallomics, 2020Co-Authors: Shehla Yousuf, Joyce E Karlinsey, Stephanie L Neville, Christopher A Mcdevitt, Stephen J Libby, Ferric C Fang, Elaine R FrawleyAbstract:Nitric oxide (NO˙) is a radical molecule produced by mammalian phagocytic cells as part of the innate immune response to bacterial pathogens. It exerts its antimicrobial activity in part by impairing the function of metalloproteins, particularly those containing iron and zinc cofactors. The pathogenic Gram-negative bacterium Salmonella enterica serovar typhimurium undergoes dynamic changes in its cellular content of the four most common metal cofactors following exposure to NO˙ Stress. Zinc, iron and magnesium all decrease in response to NO˙ while cellular manganese increases significantly. Manganese acquisition is driven primarily by increased expression of the mntH and sitABCD transporters following derepression of MntR and Fur. ZupT also contributes to manganese acquisition in response to Nitrosative Stress. S. Typhimurium mutants lacking manganese importers are more sensitive to NO˙, indicating that manganese is important for resistance to Nitrosative Stress.
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the nsrr regulon in Nitrosative Stress resistance of salmonella enterica serovar typhimurium
Molecular Microbiology, 2012Co-Authors: Joyce E Karlinsey, Elaine R Frawley, Iel Soo Bang, Lynne A Becker, Steffen Porwollik, Hannah Robbins, Vinai Chittezham Thomas, Rodolfo Urbano, Michael Mcclelland, Ferric C FangAbstract:Nitric oxide (NO·) is an important mediator of innate immunity. The facultative intracellular pathogen Salmonella has evolved mechanisms to detoxify and evade the antimicrobial actions of host-derived NO· produced during infection. Expression of the NO·-detoxifying flavohaemoglobin Hmp is controlled by the NO·-sensing transcriptional repressor NsrR and is required for Salmonella virulence. In this study we show that NsrR responds to very low NO· concentrations, suggesting that it plays a primary role in the Nitrosative Stress response. Additionally, we have defined the NsrR regulon in Salmonella enterica sv. Typhimurium 14028s using transcriptional microarray, qRT-PCR and in silico methods. A novel NsrR-regulated gene designated STM1808 has been identified, along with hmp, hcp-hcr, yeaR-yoaG, ygbA and ytfE. STM1808 and ygbA are important for S. Typhimurium growth during Nitrosative Stress, and the hcp-hcr locus plays a supportive role in NO· detoxification. ICP-MS analysis of purified STM1808 suggests that it is a zinc metalloprotein, with histidine residues H32 and H82 required for NO· resistance and zinc binding. Moreover, STM1808 and ytfE promote Salmonella growth during systemic infection of mice. Collectively, these findings demonstrate that NsrR-regulated genes in addition to hmp are important for NO· detoxification, Nitrosative Stress resistance and Salmonella virulence.
Pal Pacher - One of the best experts on this subject based on the ideXlab platform.
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cannabinoid 2 receptor limits inflammation oxidative Nitrosative Stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Abstract Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/Nitrosative Stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of cannabinoid-2 (CB 2 ) receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB 2 receptors in cisplatin-induced nephrotoxicity using the selective CB 2 receptor agonist HU-308 and CB 2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB 2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/Nitrosative Stress, and cell death in the kidney and improved renal function, whereas CB 2 knockouts developed enhanced inflammation and tissue injury. Thus, the endocannabinoid system, through CB 2 receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/Nitrosative Stress, and selective CB 2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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cannabinoid 2 receptor limits inflammation oxidative Nitrosative Stress and cell death in nephropathy
Free Radical Biology and Medicine, 2010Co-Authors: Partha Mukhopadhyay, Mohanraj Rajesh, Hao Pan, Vivek Patel, Bani Mukhopadhyay, Sandor Batkai, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/Nitrosative Stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of cannabinoid-2 (CB(2)) receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) receptors in cisplatin-induced nephrotoxicity using the selective CB(2) receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/Nitrosative Stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endocannabinoid system, through CB(2) receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/Nitrosative Stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
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cannabidiol attenuates cisplatin induced nephrotoxicity by decreasing oxidative Nitrosative Stress inflammation and cell death
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Hao Pan, Partha Mukhopadhyay, Mohanraj Rajesh, Vivek Patel, Bani Mukhopadhyay, Bin Gao, Gyorgy Hasko, Pal PacherAbstract:The platinum compound cisplatin is one of the most potent chemotherapy agents available to treat various malignancies. Nephrotoxicity is a common complication of cisplatin chemotherapy, which involves increased oxidative and Nitrosative Stress, limiting its clinical use. In this study, we have investigated the effects of a nonpsychoactive cannabinoid cannabidiol, which was reported to exert antioxidant effects and has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients in a mouse model of cisplatin-induced nephropathy. Cisplatin induced increased expression of superoxide-generating enzymes RENOX (NOX4) and NOX1, enhanced reactive oxygen species generation, inducible nitric-oxide synthase expression, nitrotyrosine formation, apoptosis (caspase-3/7 activity, DNA fragmentation, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), poly(ADP-ribose) polymerase activity, and inflammation (tumor necrosis factor-α and interleukin-1β) in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum blood urea nitrogen and creatinine levels) 72 h after the administration of the drug. Treatment of mice with cannabidiol markedly attenuated the cisplatin-induced oxidative/Nitrosative Stress, inflammation, and cell death in the kidney, and it improved renal function. Thus, our results suggest that cannabidiol may represent a promising new protective strategy against cisplatin-induced nephrotoxicity.
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oxidative Nitrosative Stress and poly adp ribose polymerase parp activation in experimental diabetic neuropathy the relation is revisited
Diabetes, 2005Co-Authors: Irina G Obrosova, Pal Pacher, Viktor R Drel, Olga Ilnytska, Zhong Q Wang, Martin J Stevens, Mark A YorekAbstract:Poly(ADP-ribose) polymerase (PARP) activation, an important factor in the pathogenesis of diabetes complications, is considered a downstream effector of oxidative-Nitrosative Stress. However, some recent findings suggest that it is not necessarily the case and that PARP activation may precede and contribute to free radical and oxidant-induced injury. This study evaluated the effect of PARP inhibition on oxidative-Nitrosative Stress in diabetic peripheral nerve, vasa nervorum, aorta, and high glucose–exposed human Schwann cells. In vivo experiments were performed in control rats and streptozocin (STZ)-induced diabetic rats treated with and without the PARP inhibitor 3-aminobenzamide (ABA) (30 mg · kg −1 · day −1 i.p. for 2 weeks after 2 weeks of untreated diabetes). Human Schwann cells (HSC) (passages 7–10; ScienCell Research Labs) were cultured in 5.5 or 30 mmol/l glucose with and without 5 mmol/l ABA. Diabetes-induced increase in peripheral nerve nitrotyrosine immunoreactivity, epineurial vessel superoxide and nitrotyrosine immunoreactivities, and aortic superoxide production was reduced by ABA. PARP-1 (Western blot analysis) was abundantly expressed in HSC, and its expression was not affected by high glucose or ABA treatment. High-glucose–induced superoxide production and overexpression of nitrosylated and poly(ADP-ribosyl)ated protein, chemically reduced amino acid-(4)-hydroxynonenal adducts, and inducible nitric oxide synthase were decreased by ABA. We concluded that PARP activation contributes to superoxide anion radical and peroxynitrite formation in peripheral nerve, vasa nervorum, and aorta of STZ-induced diabetic rats and high- glucose–exposed HSC. The relations between oxidative-Nitrosative Stress and PARP activation in diabetes are bi- rather than unidirectional, and PARP activation cannot only result from but also lead to free radical and oxidant generation.
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role of oxidative Nitrosative Stress and downstream pathways in various forms of cardiomyopathy and heart failure
Current Vascular Pharmacology, 2005Co-Authors: Zoltan Ungvari, Sandor Batkai, Sachin A Gupte, Fabio A Recchia, Pal PacherAbstract:Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and Nitrosative Stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/Nitrosative Stress and downstream pathways in various forms of cardiomyopathy and heart failure.