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Payne FM, Dabb AR, Harrison JC, Sammut IA. Inhibitors of NLRP3 Inflammasome Formation: A Cardioprotective Role for the Gasotransmitters Carbon Monoxide, Nitric Oxide, and Hydrogen Sulphide in Acute Myocardial Infarction. Int J Mol Sci 2024; 25:9247. [PMID: 39273196 PMCID: PMC11395567 DOI: 10.3390/ijms25179247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation.
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Affiliation(s)
- Fergus M Payne
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Alisha R Dabb
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Joanne C Harrison
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Ivan A Sammut
- Department of Pharmacology and Toxicology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
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2
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Dai H, Wang M, Patel PN, Kalogeris T, Liu Y, Durante W, Korthuis RJ. Preconditioning with the BK Ca channel activator NS-1619 prevents ischemia-reperfusion-induced inflammation and mucosal barrier dysfunction: roles for ROS and heme oxygenase-1. Am J Physiol Heart Circ Physiol 2017; 313:H988-H999. [PMID: 28822969 DOI: 10.1152/ajpheart.00620.2016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 07/25/2017] [Accepted: 08/07/2017] [Indexed: 12/12/2022]
Abstract
Activation of large-conductance Ca2+-activated K+ (BKCa) channels evokes cell survival programs that mitigate intestinal ischemia and reperfusion (I/R) inflammation and injury 24 h later. The goal of the present study was to determine the roles of reactive oxygen species (ROS) and heme oxygenase (HO)-1 in delayed acquisition of tolerance to I/R induced by pretreatment with the BKCa channel opener NS-1619. Superior mesentery arteries were occluded for 45 min followed by reperfusion for 70 min in wild-type (WT) or HO-1-null (HO-1-/-) mice that were pretreated with NS-1619 or saline vehicle 24 h earlier. Intravital microscopy was used to quantify the numbers of rolling and adherent leukocytes. Mucosal permeability, tumor necrosis factor-α (TNF-α) levels, and HO-1 activity and expression in jejunum were also determined. I/R induced leukocyte rolling and adhesion, increased intestinal TNF-α levels, and enhanced mucosal permeability in WT mice, effects that were largely abolished by pretreatment with NS-1619. The anti-inflammatory and mucosal permeability-sparing effects of NS-1619 were prevented by coincident treatment with the HO-1 inhibitor tin protoporphyrin-IX or a cell-permeant SOD mimetic, Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), in WT mice. NS-1619 also increased jejunal HO-1 activity in WT animals, an effect that was attenuated by treatment with the BKCa channel antagonist paxilline or MnTBAP. I/R also increased postischemic leukocyte rolling and adhesion and intestinal TNF-α levels in HO-1-/- mice to levels comparable to those noted in WT animals. However, NS-1619 was ineffective in preventing these effects in HO-1-deficient mice. In summary, our data indicate that NS-1619 induces the development of an anti-inflammatory phenotype and mitigates postischemic mucosal barrier disruption in the small intestine by a mechanism that may involve ROS-dependent HO-1 activity.NEW & NOTEWORTHY Antecedent treatment with the large-conductance Ca2+-activated K+ channel opener NS-1619 24 h before ischemia-reperfusion limits postischemic tissue injury by an oxidant-dependent mechanism. The present study shows that NS-1619-induced oxidant production prevents ischemia-reperfusion-induced inflammation and mucosal barrier disruption in the small intestine by provoking increases in heme oxygenase-1 activity.
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Affiliation(s)
- Hongyan Dai
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
| | - Meifang Wang
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
| | - Parag N Patel
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
| | - Theodore Kalogeris
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
| | - Yajun Liu
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
| | - William Durante
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
| | - Ronald J Korthuis
- Department of Medical Pharmacology and Physiology and Dalton Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, Missouri
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Ramagiri S, Taliyan R. Protective effect of remote limb post conditioning via upregulation of heme oxygenase-1/BDNF pathway in rat model of cerebral ischemic reperfusion injury. Brain Res 2017; 1669:44-54. [DOI: 10.1016/j.brainres.2017.05.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 05/10/2017] [Accepted: 05/15/2017] [Indexed: 12/16/2022]
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Wang H, Li YY, Qiu LY, Yan YF, Liao ZP, Chen HP. Involvement of DJ‑1 in ischemic preconditioning‑induced delayed cardioprotection in vivo. Mol Med Rep 2016; 15:995-1001. [PMID: 28035392 DOI: 10.3892/mmr.2016.6091] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 12/01/2016] [Indexed: 11/06/2022] Open
Abstract
DJ‑1 protein, as a multifunctional intracellular protein, has been demonstrated to serve a critical role in regulating cell survival and oxidative stress. To provide in vivo evidence that DJ‑1 is involved in the delayed cardioprotection induced by ischemic preconditioning (IPC) against oxidative stress caused by ischemia/reperfusion (I/R), the present study subjected male Sprague‑Dawley rats to IPC (3 cycles of 5‑min coronary occlusion/5‑min reperfusion) 24 h prior to I/R (30‑min coronary occlusion/120‑min reperfusion). A lentiviral vector containing short hairpin RNA was injected into the left ventricle three weeks prior to IPC, to knockdown DJ‑1 in situ. Lactate dehydrogenase (LDH) and creatine kinase‑MB (CK‑MB) release, infarct size, cardiac function, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities, malondialdehyde (MDA), intracellular reactive oxygen species (ROS), and DJ‑1 protein expression levels were assessed. IPC caused a significant increase in the expression levels of DJ‑1 protein. In addition, IPC reduced LDH and CK‑MB release, attenuated myocardial infarct size, improved cardiac function following I/R, and inhibited the elevation of ROS and MDA and the decrease in activities of the antioxidant enzymes SOD, CAT and GPx. However, in situ knockdown of DJ‑1 attenuated the IPC‑induced delayed cardioprotection, and reversed the inhibitory effect of IPC on I/R‑induced oxidative stress. The present study therefore provided novel evidence that DJ‑1 is involved in the delayed cardioprotection of IPC against I/R injury in vivo. Notably, DJ‑1 is required for IPC to inhibit I/R‑induced oxidative stress.
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Affiliation(s)
- Huan Wang
- Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yuan-Yuan Li
- Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ling-Yu Qiu
- Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yu-Feng Yan
- Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhang-Ping Liao
- Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - He-Ping Chen
- Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Beyond Preconditioning: Postconditioning as an Alternative Technique in the Prevention of Liver Ischemia-Reperfusion Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:8235921. [PMID: 27340509 PMCID: PMC4909928 DOI: 10.1155/2016/8235921] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 04/11/2016] [Accepted: 05/05/2016] [Indexed: 01/04/2023]
Abstract
Liver ischemia/reperfusion injury may significantly compromise hepatic postoperative function. Various hepatoprotective methods have been improvised, aiming at attenuating IR injury. With ischemic preconditioning (IPC), the liver is conditioned with a brief ischemic period followed by reperfusion, prior to sustained ischemia. Ischemic postconditioning (IPostC), consisting of intermittent sequential interruptions of blood flow in the early phase of reperfusion, seems to be a more feasible alternative than IPC, since the onset of reperfusion is more predictable. Regarding the potential mechanisms involved, it has been postulated that the slow intermittent oxygenation through controlled reperfusion decreases the burst production of oxygen free radicals, increases antioxidant activity, suppresses neutrophil accumulation, and modulates the apoptotic cascade. Additionally, favorable effects on mitochondrial ultrastructure and function, and upregulation of the cytoprotective properties of nitric oxide, leading to preservation of sinusoidal structure and maintenance of blood flow through the hepatic circulation could also underlie the protection afforded by postconditioning. Clinical studies are required to show whether biochemical and histological improvements afforded by the reperfusion/reocclusion cycles of postconditioning during early reperfusion can be translated to a substantial clinical benefit in liver resection and transplantation settings or to highlight more aspects of its molecular mechanisms.
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DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes. J Cardiovasc Pharmacol 2016; 66:148-58. [PMID: 25915512 DOI: 10.1097/fjc.0000000000000257] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
We have recently shown that DJ-1 is implicated in the delayed cardioprotective effect of hypoxic preconditioning (HPC) against hypoxia/reoxygenation (H/R) injury as an endogenous protective protein. This study aims to further investigate the underlying mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress. Using a well-characterized cellular model of HPC from rat heart-derived H9c2 cells, we found that HPC promoted nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein-1 (Keap1) dissociation and resulted in increased nuclear translocation, antioxidant response element-binding, and transcriptional activity of Nrf2 24 hours after HPC, with subsequent upregulation of manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1), which provided delayed protection against H/R-induced oxidative stress in normal H9c2 cells. However, the aforementioned effects of HPC were abolished in DJ-1-knockdown H9c2 cells, which were restored by restoration of DJ-1 expression. Importantly, we showed that inhibition of the Nrf2 pathway in H9c2 cells mimicked the effects of DJ-1 knockdown and abolished HPC-derived induction of antioxidative enzymes (MnSOD and HO-1) and the delayed cardioprotection. In addition, inhibition of Nrf2 also reversed the effects of restored DJ-1 expression on induction of antioxidative enzymes and delayed cardioprotection by HPC in DJ-1-knockdown H9c2 cells. Taken together, this work revealed that activation of Nrf2 pathway and subsequent upregulation of antioxidative enzymes could be a critical mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress in H9c2 cells.
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Negi G, Nakkina V, Kamble P, Sharma SS. Heme oxygenase-1, a novel target for the treatment of diabetic complications: focus on diabetic peripheral neuropathy. Pharmacol Res 2015; 102:158-67. [PMID: 26432957 DOI: 10.1016/j.phrs.2015.09.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 09/01/2015] [Accepted: 09/18/2015] [Indexed: 01/07/2023]
Abstract
Diabetic neuropathy is a complex disorder induced by long standing diabetes. Many signaling pathways and transcription factors have been proposed to be involved in the development and progression of related processes. Years of research points to critical role of oxidative stress, neuroinflammation and apoptosis in the pathogenesis of neuropathy in diabetes. Heme oxygenase-1 (HO-1) is heat-shock protein induced under conditions of different kinds of stress and has been implicated in cellular defense against oxidative stress. HO-1 degrades heme to biliverdin, carbon monoxide (CO) and free iron. Biliverdin and CO are gaining particular interest because these two have been found to mediate most of anti-inflammatory, antioxidant and anti-apoptotic effects of HO-1. Although extensively studied in different kinds of cancers and cardiovascular conditions, role of HO-1 in diabetic neuropathy is still under investigation. In this paper, we review the unique therapeutic potential of HO-1 and its role in mitigating various pathological processes that lead to diabetic neuropathy. This review also highlights the therapeutic approaches such as pharmacological and natural inducers of HO-1, gene delivery of HO-1 or its reaction products that in future, could lead to progression of HO-1 activators through the preclinical stages of drug development to clinical trials.
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Affiliation(s)
- Geeta Negi
- Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India
| | - Vanaja Nakkina
- Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India
| | - Pallavi Kamble
- Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India
| | - Shyam S Sharma
- Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
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Muscari C, Giordano E, Bonafè F, Govoni M, Pasini A, Guarnieri C. Molecular mechanisms of ischemic preconditioning and postconditioning as putative therapeutic targets to reduce tumor survival and malignancy. Med Hypotheses 2013; 81:1141-5. [PMID: 24230458 DOI: 10.1016/j.mehy.2013.10.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Revised: 09/19/2013] [Accepted: 10/20/2013] [Indexed: 10/26/2022]
Abstract
In tumors intermittent hypoxia has been reported to be more representative than normoxia or continuous exposure to low oxygen concentrations. Intermittent hypoxia is thought to increase tumor resistance against both anti-cancer therapy and the sustained ischemia that randomly occurs because of the dynamic nature of tumor vasculature. Here, we hypothesize that the molecular mechanisms underlying intermittent hypoxia in tumor cells share some triggers, modulators, and end-effectors of the intermittent episodes of ischemia and reperfusion that characterize ischemic preconditioning and postconditioning. These are among the most effective maneuvers protecting cells from ischemia-reperfusion injury. If this hypothesis were confirmed, several well-investigated molecular mediators of pre/post-conditioning could be explored as therapeutic targets against tumor malignancy. For examples, drugs that completely block the cardioprotection induced by ischemic preconditioning, such as mitochondrial potassium ATP channel inhibitors or mitochondrial permeability transition pore openers, could be extraordinarily efficient in counteracting the adaptations of tumor cells and cancer stem cells to intermittent hypoxia. As a consequence, this strategy should be effective in blunting tumor capacity to progress toward malignancy and survive in ischemic conditions.
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Affiliation(s)
- Claudio Muscari
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; National Institute for Cardiovascular Research, Bologna, Italy; BioEngLab, Health Science and Technology-Interdepartmental Center for Industrial Research (HST-CIRI), University of Bologna, Ozzano Emilia (BO), Italy.
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Huang XS, Chen HP, Yu HH, Yan YF, Liao ZP, Huang QR. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection. Mol Cell Biochem 2013; 385:33-41. [PMID: 24048861 DOI: 10.1007/s11010-013-1812-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 09/12/2013] [Indexed: 12/19/2022]
Abstract
It has been well demonstrated that hypoxic preconditioning (HPC) can attenuate hypoxia/reoxygenation (H/R)-induced oxidant stress and elicit delayed cardioprotection by upregulating the expression of multiple antioxidative enzymes such as heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD) and so on. However, the underlying mechanisms of HPC-induced upregulation of antioxidative enzymes are not fully understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element (ARE) and plays a crucial role in cellular defence against oxidative stress. Here, we wondered whether activation of the Nrf2-ARE pathway is responsible for the induction of antioxidative enzymes by HPC and contributes to the delayed cardioprotection of HPC. Cellular model of HPC from rat heart-derived H9c2 cells was induced 24 h prior to H/R. The results showed that HPC efficiently attenuated H/R-induced viability loss and lactate dehydrogenase leakage. In addition, HPC increased nuclear translocation and ARE binding of Nrf2 during the late phase, upregulated the expression of antioxidative enzymes (HO-1 and MnSOD), inhibited H/R-induced oxidant stress. However, when Nrf2 was specifically knocked down by siRNA, the induction of antioxidative enzymes by HPC was completely abolished and, as a result, the inhibitory effect of HPC on H/R-induced oxidant stress was reversed, and the delayed cardioprotection induced by HPC was also abolished. These results suggest that HPC upregulates antioxidative enzymes through activating the Nrf2-ARE pathway and confers delayed cardioprotection against H/R-induced oxidative stress.
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Affiliation(s)
- Xiao-Shan Huang
- The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, People's Republic of China
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Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. ACTA ACUST UNITED AC 2013. [DOI: 10.4199/c00090ed1v01y201309isp044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Jiang B, Zhang B, Liang P, Chen G, Zhou B, Lv C, Tu Z, Xiao X. Nucleolin protects the heart from ischaemia-reperfusion injury by up-regulating heat shock protein 32. Cardiovasc Res 2013; 99:92-101. [PMID: 23594402 DOI: 10.1093/cvr/cvt085] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS Nucleolin plays important roles in a variety of cellular processes. In this study, we aimed to investigate the role of nucleolin in cardiac ischaemia-reperfusion (I-R) injury. METHODS AND RESULTS We investigated the expression pattern of nucleolin in hearts subjected to I-R, or neonatal rat cardiomyocytes subjected to hypoxia-re-oxygenation. We found that nucleolin expression was significantly down-regulated and the cleaved protein was present, both in vivo and in vitro. Gene transfection and RNA interference approaches were employed in cardiomyocytes to investigate the function of nucleolin. Over-expression of nucleolin was cytoprotective, whereas nucleolin ablation enhanced both hypoxia- and H₂O₂-induced cardiomyocyte death. Furthermore, transgenic mice with cardiac-specific over-expression of nucleolin were resistant to I-R injury as indicated by decreased cellular necrosis and decreased infarct size. The cardio-protective roles of nucleolin in cardiomyocytes, are attributable to the interaction of nucleolin with the mRNA of heat shock protein 32 (Hsp32), resulting in an increase of Hsp32 mRNA stability, and subsequent up-regulation of Hsp32 expression. The selective Hsp32 inhibitor, zinc protoporphyrin-IX, abrograted the cardiac protection mediated by nucleolin. CONCLUSION This study has demonstrated that nucleolin is involved in the regulation of I-R-induced cardiac injury and dysfunction via the regulation of Hsp32, and may be a novel therapeutic target for ischaemic heart diseases.
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MESH Headings
- 3' Untranslated Regions
- Animals
- Animals, Newborn
- Binding Sites
- Cell Death
- Cell Hypoxia
- Cells, Cultured
- Computational Biology
- Disease Models, Animal
- Enzyme Inhibitors/pharmacology
- Gene Expression Profiling/methods
- Gene Expression Regulation, Enzymologic
- Genes, Reporter
- Heme Oxygenase (Decyclizing)/antagonists & inhibitors
- Heme Oxygenase (Decyclizing)/genetics
- Heme Oxygenase (Decyclizing)/metabolism
- Heme Oxygenase-1/antagonists & inhibitors
- Heme Oxygenase-1/genetics
- Heme Oxygenase-1/metabolism
- Male
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Myocardial Reperfusion Injury/enzymology
- Myocardial Reperfusion Injury/genetics
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/prevention & control
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/pathology
- Oligonucleotide Array Sequence Analysis
- Oxidants/toxicity
- Phosphoproteins/genetics
- Phosphoproteins/metabolism
- RNA Interference
- RNA Stability
- RNA, Messenger/metabolism
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Time Factors
- Transfection
- Up-Regulation
- Nucleolin
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Affiliation(s)
- Bimei Jiang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China
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Transcriptome analysis of renal ischemia/reperfusion injury and its modulation by ischemic pre-conditioning or hemin treatment. PLoS One 2012; 7:e49569. [PMID: 23166714 PMCID: PMC3498198 DOI: 10.1371/journal.pone.0049569] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 10/10/2012] [Indexed: 01/06/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) is a leading cause of acute renal failure. The definition of the molecular mechanisms involved in renal IRI and counter protection promoted by ischemic pre-conditioning (IPC) or Hemin treatment is an important milestone that needs to be accomplished in this research area. We examined, through an oligonucleotide microarray protocol, the renal differential transcriptome profiles of mice submitted to IRI, IPC and Hemin treatment. After identifying the profiles of differentially expressed genes observed for each comparison, we carried out functional enrichment analysis to reveal transcripts putatively involved in potential relevant biological processes and signaling pathways. The most relevant processes found in these comparisons were stress, apoptosis, cell differentiation, angiogenesis, focal adhesion, ECM-receptor interaction, ion transport, angiogenesis, mitosis and cell cycle, inflammatory response, olfactory transduction and regulation of actin cytoskeleton. In addition, the most important overrepresented pathways were MAPK, ErbB, JAK/STAT, Toll and Nod like receptors, Angiotensin II, Arachidonic acid metabolism, Wnt and coagulation cascade. Also, new insights were gained about the underlying protection mechanisms against renal IRI promoted by IPC and Hemin treatment. Venn diagram analysis allowed us to uncover common and exclusively differentially expressed genes between these two protective maneuvers, underscoring potential common and exclusive biological functions regulated in each case. In summary, IPC exclusively regulated the expression of genes belonging to stress, protein modification and apoptosis, highlighting the role of IPC in controlling exacerbated stress response. Treatment with the Hmox1 inducer Hemin, in turn, exclusively regulated the expression of genes associated with cell differentiation, metabolic pathways, cell cycle, mitosis, development, regulation of actin cytoskeleton and arachidonic acid metabolism, suggesting a pleiotropic effect for Hemin. These findings improve the biological understanding of how the kidney behaves after IRI. They also illustrate some possible underlying molecular mechanisms involved in kidney protection observed with IPC or Hemin treatment maneuvers.
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Lu HS, Chen HP, Wang S, Yu HH, Huang XS, Huang QR, He M. Hypoxic preconditioning up-regulates DJ-1 protein expression in rat heart-derived H9c2 cells through the activation of extracellular-regulated kinase 1/2 pathway. Mol Cell Biochem 2012; 370:231-40. [PMID: 22878563 DOI: 10.1007/s11010-012-1414-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 08/01/2012] [Indexed: 11/25/2022]
Abstract
Myocardial preconditioning is a powerful phenomenon that can attenuate ischemia/reperfusion-induced oxidant stress and elicit delayed cardioprotection. Its mechanisms involve activation of intracellular signaling pathways and up-regulation of the protective antioxidant proteins. DJ-1 protein, as a multifunctional intracellular protein, plays an important role in attenuating oxidant stress and promoting cell survival. In the present study, we investigated whether DJ-1 is up-regulated during the late phase of hypoxic preconditioning (HP) and the up-regulation of DJ-1 is mediated by extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway. Rat heart-derived H9c2 cells were exposed to HP. Twenty-four hours later cells were subjected to hypoxia/reoxygenation (H/R) and then cell viability, lactate dehydrogenase (LDH), intracellular reactive oxygen species (ROS), ERK1/2 phosphorylation, and DJ-1 protein were measured appropriately. The results showed that HP efficiently attenuated H/R-induced viability loss and LDH leakage. In addition, HP promoted ERK1/2 activation, up-regulated DJ-1 protein expression, inhibited H/R induced the elevation of ROS. However, when ERK1/2 phosphorylation was specifically inhibited by U0126, the increase in DJ-1 expression occurring during HP was almost completely abolished and, as a result, the delayed cardioprotection induced by HP was abolished, and the inhibitory effect of HP on H/R-induced oxidant stress was also reversed. Furthermore, knocking down DJ-1 by siRNA attenuated the delayed cardioprotection induced by HP. Our data indicate that HP can up-regulate DJ-1 protein expression through the ERK1/2-dependent signaling pathway. Importantly, DJ-1 might be involved in the delayed cardioprotective effect of HP against H/R injury.
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Affiliation(s)
- Hai-Shan Lu
- Department of Pharmacology & Molecular Therapeutics, School of Pharmaceutical Science, Nanchang University, Nanchang, People's Republic of China
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Ong SG, Hausenloy DJ. Hypoxia-inducible factor as a therapeutic target for cardioprotection. Pharmacol Ther 2012; 136:69-81. [PMID: 22800800 DOI: 10.1016/j.pharmthera.2012.07.005] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 06/18/2012] [Indexed: 10/28/2022]
Abstract
Hypoxia inducible factor (HIF) is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia. This is achieved through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Under conditions of normoxia, the hydroxylation of HIF by prolyl hydroxylase domain-containing (PHD) enzymes targets it for polyubiquitination and proteosomal degradation by the von Hippel-Lindau protein (VHL). However, under hypoxic conditions, PHD activity is inhibited, thereby allowing HIF to accumulate and translocate to the nucleus, where it binds to the hypoxia-responsive element sequences of target gene promoters. Experimental studies suggest that HIF may act as a mediator of ischemic preconditioning, and that the genetic or pharmacological stabilization of HIF under normoxic conditions, may protect the heart against the detrimental effects of acute ischemia-reperfusion injury. The mechanisms underlying the cardioprotective effect of HIF are unclear, but it may be attributed to the transcriptional activation of genes associated with cardioprotection such as erythropoietin, heme oxygenase-1, and inducible nitric oxide synthase or it may be due to reprogramming of cell metabolism. In this review article, we highlight the role of HIF in mediating both adaptive and pathological processes in the heart, as well as focusing on the therapeutic potential of the HIF-signaling pathway as a target for cardioprotection.
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Affiliation(s)
- Sang-Ging Ong
- The Hatter Cardiovascular Institute, University College London Hospital, 67 Chenies Mews, London WC1E 6HX, United Kingdom
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15
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Abstract
The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.
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16
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Zeng Z, Huang HF, He F, Wu LX, Lin J, Chen MQ. Diazoxide attenuates ischemia/reperfusion injury via upregulation of heme oxygenase-1 after liver transplantation in rats. World J Gastroenterol 2012; 18:1765-72. [PMID: 22553400 PMCID: PMC3332289 DOI: 10.3748/wjg.v18.i15.1765] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 01/17/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of diazoxide on ischemia/reperfusion (I/R)-injured hepatocytes and further elucidate its underlying mechanisms.
METHODS: Male Sprague-Dawley rats were randomized (8 for donor and recipient per group) into five groups: I/R group (4 h of liver cold ischemia followed by 6 h of reperfusion); heme oxygenase-1 (HO-1) small interfering RNA (siRNA) group (injection of siRNA via donor portal vein 48 h prior to harvest); diazoxide (DZ) group (injection of DZ via donor portal vein 10 min prior to harvest); HO-1 siRNA + DZ group; and siRNA control group. Blood and liver samples were collected at 6 h after reperfusion. The mRNA expressions and protein levels of HO-1 were determined by reverse transcription polymerase chain reaction and Western blotting, and tissue morphology was examined by light and transmission electron microscopy. Serum transaminases level and cytokines concentration were also measured.
RESULTS: We observed that a significant reduction of HO-1 mRNA and protein levels in HO-1 siRNA and HO-1 siRNA + DZ group when compared with I/R group, while the increases were prominent in the DZ group. Light and transmission electron microscopy indicated severe disruption of tissue with lobular distortion and mitochondrial cristae damage in the HO-1 siRNA and HO-1 siRNA + DZ groups compared with DZ group. Serum alanine aminotransferase, aspartate transaminase, tumor necrosis factor-α and interleukin-6 levels increased in the HO-1 siRNA and HO-1 siRNA + DZ groups, and decreased in the DZ group.
CONCLUSION: The protective effect of DZ may be induced by upregulation of HO-1. By inhibiting expression of HO-1, this protection pretreated with DZ was abolished.
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17
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Heme oxygenase-1 induction and organic nitrate therapy: beneficial effects on endothelial dysfunction, nitrate tolerance, and vascular oxidative stress. Int J Hypertens 2012; 2012:842632. [PMID: 22506100 PMCID: PMC3312327 DOI: 10.1155/2012/842632] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Accepted: 11/21/2011] [Indexed: 12/21/2022] Open
Abstract
Organic nitrates are a group of very effective anti-ischemic drugs. They are used for the treatment of patients with stable angina, acute myocardial infarction, and chronic congestive heart failure. A major therapeutic limitation inherent to organic nitrates is the development of tolerance, which occurs during chronic treatment with these agents, and this phenomenon is largely based on induction of oxidative stress with subsequent endothelial dysfunction. We therefore speculated that induction of heme oxygenase-1 (HO-1) could be an efficient strategy to overcome nitrate tolerance and the associated side effects. Indeed, we found that hemin cotreatment prevented the development of nitrate tolerance and vascular oxidative stress in response to chronic nitroglycerin therapy. Vice versa, pentaerithrityl tetranitrate (PETN), a nitrate that was previously reported to be devoid of adverse side effects, displayed tolerance and oxidative stress when the HO-1 pathway was blocked pharmacologically or genetically by using HO-1+/– mice. Recently, we identified activation of Nrf2 and HuR as a principle mechanism of HO-1 induction by PETN. With the present paper, we present and discuss our recent and previous findings on the role of HO-1 for the prevention of nitroglycerin-induced nitrate tolerance and for the beneficial effects of PETN therapy.
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18
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Zeng Z, Huang HF, Chen MQ, Song F, Zhang YJ. Contributions of heme oxygenase-1 in postconditioning-protected ischemia-reperfusion injury in rat liver transplantation. Transplant Proc 2012; 43:2517-23. [PMID: 21911116 DOI: 10.1016/j.transproceed.2011.04.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Revised: 03/18/2011] [Accepted: 04/21/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Heme oxygenase-1 (HO-1), an oxidative stress-response gene up-regulated by various physiological and exogenous stimuli, has cytoprotective activities. Ischemic postconditioning (Postcon) can protect an organ from ischemia-reperfusion (I/R) injury. In the present study, we investigated the potential contributions of HO-1 to Postcon-dependent protection against I/R injury in rat liver transplantation models. MATERIALS AND METHODS Adult male Sprague-Dawley rats were randomly divided into four groups: sham group with laparotomy for liver exposure; I/R group with 24-hour cold ischemia of the donor liver; Postcon group with the same treatment as the I/R group plus ischemic Postcon; and zinc protoporphyrin (ZnPP HO-1 inhibitor) + Postcon group treated the same as the Postcon cohort with donors pretreated using ZnPP 24 hours before the I/R injury. We measured liver tissue and peripheral blood samples collected at 6 hours after reperfusion and serum transaminase levels, histopathology, liver tissue malondialdehyde (MDA) content, superoxide dismutase (SOD) activity and HO-1 expression in the liver. RESULTS Postcon significantly diminished the elevation of serum transaminases levels after I/R injury when compared with I/R and ZnPP+Postcon groups. Postcon treated rats showed significantly lower MDA production and higher SOD activity. HO-1 was induced in rat livers exposed to Postcon; its levels were obviously overexpressed after 6 hours in Postcon rats. Inhibiting the expression of HO-1, negated the protective effects of Postcon. CONCLUSIONS Induction of HO-1 in the Postcon condition played a protective role against hepatic I/R injury and enhanced the early antioxidative activity. The protective effects of Postcon were significantly associated with greater intrahepatic HO-1 expression.
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Affiliation(s)
- Z Zeng
- Organ Transplant Center, The First Affiliated Hospital of Kunming Medical College, Kunming, China.
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19
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Abstract
A standard ischemic preconditioning (IPC) stimulus of one or more brief episodes of non-lethal myocardial ischemia and reperfusion elicits a bi-phasic pattern of cardioprotection. The first phase manifests almost immediately following the IPC stimulus and lasts for 1-2 h, after which its effect disappears (termed classical or early IPC). The second phase of cardioprotection appears 12-24 h later and lasts for 48-72 h (termed the Second Window of Protection [SWOP] or delayed or late IPC). The cardioprotection conferred by delayed IPC is robust and ubiquitous but is not as powerful as early IPC. Although there are some similarities in the mechanisms underlying early and delayed IPC, one of the major distinctions between the two is the latter's requirement for de novo protein synthesis of distal mediators such as iNOS and COX-2 which mediate the cardioprotection 24 h after the IPC stimulus. The phenomenon of delayed IPC has been demonstrated in man using a variety of experimental models. However, its clinical application has been limited by the same factors which affect early IPC- i.e. the need to intervene before the onset of myocardial ischemia, thereby restricting its potential clinical utility to planned settings of acute myocardial ischemia-reperfusion injury such as coronary artery bypass graft surgery, cardiac transplantation and percutaneous coronary intervention. In this article, the focus will be on the origins of delayed IPC, the mechanisms underlying its delayed cardioprotective effect, and the potential areas for its clinical application.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
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20
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Bartz RR, Piantadosi CA. Clinical review: oxygen as a signaling molecule. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2010; 14:234. [PMID: 21062512 PMCID: PMC3219237 DOI: 10.1186/cc9185] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Molecular oxygen is obviously essential for conserving energy in a form useable for aerobic life; however, its utilization comes at a cost--the production of reactive oxygen species (ROS). ROS can be highly damaging to a range of biological macromolecules, and in the past the overproduction of these short-lived molecules in a variety of disease states was thought to be exclusively toxic to cells and tissues such as the lung. Recent basic research, however, has indicated that ROS production--in particular, the production of hydrogen peroxide--plays an important role in both intracellular and extracellular signal transduction that involves diverse functions from vascular health to host defense. The present review summarizes oxygen's capacity, acting through its reactive intermediates, to recruit the enzymatic antioxidant defenses, to stimulate cell repair processes, and to mitigate cellular damage.
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Affiliation(s)
- Raquel R Bartz
- Department of Anesthesiology, Duke University School of Medicine, Box 3094, Durham, NC 27710, USA.
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21
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Cho WY, Choi HM, Lee SY, Kim MG, Kim HK, Jo SK. The role of Tregs and CD11c(+) macrophages/dendritic cells in ischemic preconditioning of the kidney. Kidney Int 2010; 78:981-92. [PMID: 20686446 DOI: 10.1038/ki.2010.266] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Dendritic cells have the potential to induce tolerance and here we attempted to identify their role in the tolerance seen in ischemic pre-conditioning. We induced bilateral renal ischemic preconditioning in mice and then challenged them with an ischemic insult 7 days later. Compared to sham-operated controls, preconditioned mice were found to have reduced injury with less inflammation, but had an increased number of regulatory T cells (Tregs) in their kidneys after the delayed insult. Splenocytes from these mice had more Tregs and mature CD11c(+) cells, but reduced proliferative and cytokine-secretory responses, suggesting a state of immunosuppression compared to control mice. Anti-CD25 depletion followed by adoptive transfer of Tregs partially mitigated and then restored the protective effect of preconditioning. Depletion of CD11c(+) cells with liposomes containing clodronate was associated with partial loss of preconditioning benefits. The increased numbers of Tregs or impaired immune response found in splenocytes from preconditioned mice were partially reversed in splenocytes from liposome clodronate-treated animals, suggesting that CD11c(+) cells contribute to immune cell-mediated ischemic preconditioning. Hence, our results show that ischemic preconditioning of the kidney provides a negative signal to the peripheral immune system, partially mediating the tissue-protective and anti-inflammatory effects of this maneuver.
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Affiliation(s)
- Won Yong Cho
- Division of Nephrology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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22
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Tranter M, Ren X, Forde T, Wilhide ME, Chen J, Sartor MA, Medvedovic M, Jones WK. NF-kappaB driven cardioprotective gene programs; Hsp70.3 and cardioprotection after late ischemic preconditioning. J Mol Cell Cardiol 2010; 49:664-72. [PMID: 20643136 DOI: 10.1016/j.yjmcc.2010.07.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 06/30/2010] [Accepted: 07/01/2010] [Indexed: 12/14/2022]
Abstract
It has been shown that the transcription factor NF-kappaB is necessary for late phase cardioprotection after ischemic preconditioning (IPC) in the heart, and yet is injurious after ischemia/reperfusion (I/R). However the downstream gene expression programs that underlie the contribution of NF-kappaB to cardioprotection after late IPC are incompletely understood. The objective of this study was to delineate the specific genes that are regulated by NF-kappaB immediately after a late IPC stimulus and validate the methodology for the identification of NF-kappaB-dependent genes that contribute to cardioprotection. A directed microarray analysis identified 238 genes as up or downregulated in an NF-kappaB-dependent manner 3.5h after late IPC. Among these are several genes previously implicated in late IPC. Gene ontological analysis showed that the most significant group of NF-kappaB-dependent genes are heat shock response genes, including the genes encoding Hsp70.1 and Hsp70.3. Though an Hsp70.1/70.3 double knockout failed to exhibit cardioprotection, late IPC was intact in the Hsp70.1 single knockout. After I/R, the Hsp70.1/70.3 double knockout and the Hsp70.1 single knockout had significantly increased and reduced infarct size, respectively. These results delineate the immediate NF-kappaB-dependent transcriptome after late IPC. One of the major categories of NF-kappaB-dependent genes induced by late IPC is the heat shock response. The results of infarct studies confirm that Hsp70.3 is protective after IPC. However, though Hsp70.1 and Hsp70.3 are coordinately regulated, their functions are opposing after I/R injury.
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Affiliation(s)
- Michael Tranter
- Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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23
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Brief exposure to carbon monoxide preconditions cardiomyogenic cells against apoptosis in ischemia-reperfusion. Biochem Biophys Res Commun 2010; 393:449-54. [PMID: 20152804 DOI: 10.1016/j.bbrc.2010.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Accepted: 02/04/2010] [Indexed: 12/29/2022]
Abstract
We examined whether and how pretreatment with carbon monoxide (CO) prevents apoptosis of cardioblastic H9c2 cells in ischemia-reperfusion. Reperfusion (6 h) following brief ischemia (10 min) induced cytochrome c release, activation of caspase-9 and caspase-3, and apoptotic nuclear condensation. Brief CO pretreatment (10 min) or a caspase-9 inhibitor (Z-LEHD-FMK) attenuated these apoptotic changes. Ischemia-reperfusion increased phosphorylation of Akt at Ser472/473/474, and this was enhanced by CO pretreatment. A specific Akt inhibitor (API-2) blunted the anti-apoptotic effects of CO in reperfusion. In normoxic cells, CO enhanced O2(-) generation, which was inhibited by a mitochondrial complex III inhibitor (antimycin A) but not by a NADH oxidase inhibitor (apocynin). The CO-enhanced Akt phosphorylation was suppressed by an O2(-) scavenger (Tiron), catalase or a superoxide dismutase (SOD) inhibitor (DETC). These results suggest that CO pretreatment induces mitochondrial generation of O2(-), which is then converted by SOD to H2O2, and subsequent Akt activation by H2O2 attenuates apoptosis in ischemia-reperfusion.
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24
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Gori T, Dragoni S, Di Stolfo G, Sicuro S, Liuni A, Luca MC, Thomas G, Oelze M, Daiber A, Parker JD. Tolerance to nitroglycerin-induced preconditioning of the endothelium: a human in vivo study. Am J Physiol Heart Circ Physiol 2009; 298:H340-5. [PMID: 19933412 DOI: 10.1152/ajpheart.01324.2008] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Damage and dysfunction of the vascular endothelium critically influence clinical outcomes after ischemia and reperfusion (I/R). Brief exposure to organic nitrates can protect the vascular endothelium from I/R injury via a mechanism that is similar to ischemic preconditioning and is independent of hemodynamic changes. The clinical relevance of these protective effects clearly depends on whether they can be sustained over time. Twenty-four healthy (age 25-32) male volunteers were randomized to receive 1) transdermal nitroglycerin (GTN; 0.6 mg/h) administered for 2 h on 1 day only, 2) transdermal GTN for 2 h/day for 7 days, or 3) continuous therapy with transdermal GTN for 7 days. Eight volunteers underwent continuous GTN therapy followed by intra-arterial infusion of the antioxidant vitamin C. Finally, five additional subjects underwent no therapy and served as controls. Endothelial function measurements were performed before and after induction of I/R of the arm. I/R caused a significant blunting of the flow responses to acetylcholine in the control group (P < 0.01 vs. before I/R). A single 2-h GTN dosage, given 24 h before I/R, prevented I/R-induced endothelial dysfunction [P = not significant (NS) vs. before I/R], but this protective effect was completely lost after 1 wk of GTN administration 2 h/day (P < 0.05 vs. before I/R; P = NS vs. control). In subjects who received continuous GTN, endothelial responses were blunted before I/R, and I/R did not cause further endothelial dysfunction. Finally, vitamin C normalized acetylcholine responses and prevented the loss of preconditioning associated with prolonged GTN. In a separate experimental model using isolated human endothelial cells, short-term incubation with GTN caused upregulation of heme oxygenase, an effect that was lost after prolonged GTN administration. Although a single administration of GTN is able to protect the endothelium from I/R-induced endothelial dysfunction, this protection is lost upon prolonged exposure, likely via an oxidative mechanism.
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Affiliation(s)
- Tommaso Gori
- Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Italy.
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25
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Reichelt ME, Shanu A, Willems L, Witting PK, Ellis NA, Blackburn MR, Headrick JP. Endogenous adenosine selectively modulates oxidant stress via the A1 receptor in ischemic hearts. Antioxid Redox Signal 2009; 11:2641-50. [PMID: 19552606 PMCID: PMC2861535 DOI: 10.1089/ars.2009.2644] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We tested the impact of A1 adenosine receptor (AR) deletion on injury and oxidant damage in mouse hearts subjected to 25-min ischemia/45-min reperfusion (I/R). Wild-type hearts recovered approximately 50% of contractile function and released 8.2 +/- 0.7 IU/g of lactate dehydrogenase (LDH). A1AR deletion worsened dysfunction and LDH efflux (15.2 +/- 2.6 IU/g). Tissue cholesterol and native cholesteryl esters were unchanged, whereas cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased threefold, and alpha-tocopherylquinone [alpha-TQ; oxidation product of alpha-tocopherol (alpha-TOH)] increased sixfold. Elevations in alpha-TQ were augmented by two- to threefold by A1AR deletion, whereas CE-O(O)H was unaltered. A(1)AR deletion also decreased glutathione redox status ([GSH]/[GSSG + GSH]) and enhanced expression of the antioxidant response element heme oxygenase-1 (HO-1) during I/R: fourfold elevations in HO-1 mRNA and activity were doubled by A1AR deletion. Broad-spectrum AR agonism (10 microM 2-chloroadenosine; 2-CAD) countered effects of A1AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A(2A), A(2B), and/or A3) can mediate similar actions. These data reveal that local adenosine engages A1ARs during I/R to limit oxidant damage and enhance outcome selectively. Control of alpha-TOH/alpha-TQ levels may contribute to A1AR-dependent cardioprotection.
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Affiliation(s)
- Melissa E Reichelt
- Heart Foundation Research Center, Griffith University , Southport, Queensland, Australia.
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26
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Gori T, Daiber A. Non-hemodynamic effects of organic nitrates and the distinctive characteristics of pentaerithrityl tetranitrate. Am J Cardiovasc Drugs 2009; 9:7-15. [PMID: 19178128 DOI: 10.1007/bf03256591] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Organic nitrates are among the oldest and yet most commonly employed drugs in the long-term therapy of coronary artery disease and congestive heart failure. While they have long been used in clinical practice, our understanding of their mechanism of action and side effects remains incomplete. For instance, recent findings provide evidence of previously unanticipated, non-hemodynamic properties that include potentially beneficial mechanisms (such as the induction of a protective phenotype that mimics ischemic preconditioning), but also toxic effects (such as endothelial and autonomic dysfunction, rebound angina, tolerance). To date, the most commonly employed organic nitrates are isosorbide mononitrate, isosorbide dinitrate, and nitroglycerin (glyceryl trinitrate). Another organic nitrate, pentaerithrityl tetranitrate (PETN), has long been employed in eastern European countries and is currently being reintroduced in Western countries. In light of their wide use, and of the (re)introduction of PETN in Western markets, the present review focuses on the novel effects of organic nitrates, describing their potential clinical implications and discussing differences among different compounds. We believe that these recent findings have important clinical implications. Since the side effects of organic nitrates such as nitroglycerin and isosorbides appear to be mediated by reactive oxygen species, care should be taken that drugs with antioxidant properties are co-administered. On the other hand, efforts should be made to clinically exploit the preconditioning effects of these drugs.
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27
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Zeynalov E, Shah ZA, Li RC, Doré S. Heme oxygenase 1 is associated with ischemic preconditioning-induced protection against brain ischemia. Neurobiol Dis 2009; 35:264-9. [PMID: 19465127 DOI: 10.1016/j.nbd.2009.05.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 05/12/2009] [Accepted: 05/15/2009] [Indexed: 02/01/2023] Open
Abstract
Ischemic preconditioning (IPC) protects brain against ischemic injury by activating specific mechanisms. Our goal was to determine if the inducible heme oxygenase 1 (HO1) is required for such protection. IPC before transient or permanent ischemia reduced cortical infarct volumes by 57.4% and 33.9%, respectively at 48 h in wildtype adult mice. Interestingly, IPC failed to protect the HO1 gene deleted mice against permanent ischemic brain injury. IPC also resulted in a significant increase in HO1 protein levels in the brain and correlated with reduced neurological deficits after permanent and transient brain ischemia. Our study demonstrates that neuroprotective effects of IPC are at least partially mediated via HO1. Elucidating the physiological/cellular role by which HO1 is protective against brain ischemia may aid the development of selective drugs to treat stroke and its associated neurological disorders.
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Affiliation(s)
- Emil Zeynalov
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 365, Baltimore, MD 21205, USA
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28
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Zhu XY, Daghini E, Chade AR, Versari D, Krier JD, Textor KB, Lerman A, Lerman LO. Myocardial microvascular function during acute coronary artery stenosis: effect of hypertension and hypercholesterolaemia. Cardiovasc Res 2009; 83:371-80. [PMID: 19423617 DOI: 10.1093/cvr/cvp140] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS Coronary collateral arteries (CCA) reduce cardiovascular events. We tested the hypothesis that new microvessels that proliferate in early atherosclerosis may be associated with myocardial protection during acute subtotal coronary artery obstruction (CAO). METHODS AND RESULTS Acute left anterior descending CAO was induced by a balloon catheter in pigs after 12 weeks of high-cholesterol (HC) diet, renovascular hypertension (HTN), or normal control. Cardiac structure, myocardial perfusion, and functional response to iv adenosine and CAO were studied in vivo using electron beam computed tomography (CT). The intra-myocardial microvessels were subsequently evaluated ex vivo using micro-CT, and myocardial expression of growth factors using immunoblotting. Basal myocardial perfusion and microvascular permeability were similar among the groups, whereas their responses to adenosine were attenuated in HC and HTN. A significant decline in myocardial perfusion in normal pigs during acute CAO was attenuated in HC and abolished in HTN. CAO also elicited an increase in normal anterior wall microvascular permeability (+202 +/- 59%, P < 0.05), which was attenuated in HC and HTN (+55 +/- 9 and +31 +/- 8%, respectively, P < 0.05 vs. normal). Microvascular (<200 microm) spatial density was significantly elevated in HC and HTN, accompanied by increased myocardial growth factor expression. CONCLUSION This study demonstrates that early exposure to the cardiovascular risk factors HC and HTN protects the heart from decreases in myocardial perfusion during acute subtotal CAO. This protective effect is associated with and potentially mediated by pre-emptive development of intra-myocardial microvessels that might serve as recruitable CCA.
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Affiliation(s)
- Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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29
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Gaskin FS, Kamada K, Yusof M, Durante W, Gross G, Korthuis RJ. AICAR preconditioning prevents postischemic leukocyte rolling and adhesion: role of K(ATP) channels and heme oxygenase. Microcirculation 2009; 16:167-76. [PMID: 19152177 DOI: 10.1080/10739680802355897] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE We previously demonstrated that pharmacologic activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) 24 hours prior to (AICAR preconditioning; AICAR-PC) ischemia/reperfusion (I/R) prevents postischemic leukocyte-endothelial cell adhesive interactions (LEI) by a mechanism initiated by endothelial nitric oxide synthase (eNOS)-dependent NO production during the period of AICAR-PC. The major aim of this study was to examine the role of ATP-sensitive potassium (K(ATP)) channels and heme oxygenase as mediators of the antiadhesive effects of AICAR-PC during I/R 24 hours later. METHODS Intravital fluorescence microscopy was used to quantify LEI in the small intestine of AICAR-preconditioned C57BL/6J mice treated with K(ATP) channel or heme oxygenase inhibitors during I/R 24 hours after AICAR-PC in separate experiments. RESULTS I/R induced marked increases in LEI relative to sham control mice, proadhesive responses that were prevented by AICAR-PC 24 hours prior to I/R. The effects of AICAR-PC to prevent postischemic LEI were abolished by K(ATP) channel or heme oxygenase inhibition during I/R. DISCUSSION/CONCLUSION Our results indicate that the antiadhesive effects of AICAR-PC are mediated by K(ATP) channel- and heme oxygenase-dependent mechanisms during I/R.
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Affiliation(s)
- F Spencer Gaskin
- Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, One Hospital Drive, Columbia, MO 65212, USA
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Hypoxia-inducible factor 1 and related gene products in anaesthetic-induced preconditioning. Eur J Anaesthesiol 2009; 26:201-6. [DOI: 10.1097/eja.0b013e3283212cbb] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Mechanisms of flavonoid protection against myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 2008; 46:309-17. [PMID: 19133271 DOI: 10.1016/j.yjmcc.2008.12.003] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2008] [Revised: 12/04/2008] [Accepted: 12/05/2008] [Indexed: 01/10/2023]
Abstract
Flavonoids have long been acknowledged for their unique antioxidant properties, and possess other activities that may be relevant to heart ischemia-reperfusion. They may prevent production of oxidants (e.g. by inhibition of xanthine oxidase and chelation of transition metals), inhibit oxidants from attacking cellular targets (e.g. by electron donation and scavenging activities), block propagation of oxidative reactions (by chain-breaking antioxidant activity), and reinforce cellular antioxidant capacity (through sparing effects on other antioxidants and inducing expression of endogenous antioxidants). Flavonoids also possess anti-inflammatory and anti-platelet aggregation effects through inhibiting relevant enzymes and signaling pathways, resulting ultimately in lower oxidant production and better re-establishment of blood in the ischemic zone. Finally, flavonoids are vasodilatory through a variety of mechanisms, one of which is likely interaction with ion channels. These multifaceted activities of flavonoids raise their utility as possible therapeutic interventions to ameliorate ischemia-reperfusion injury.
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Geraldine J, Mala S, Takeuchi S. Heat Shock Proteins in Cardiovascular Stress. Clin Med Cardiol 2008. [DOI: 10.4137/cmc.s876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- John Geraldine
- Factory of Takeuchi Nenshi, TAKENEN, 85 NE, Takamatsu, Kahoku, Ishikawa-929-1215, Japan
| | - Sandana Mala
- Factory of Takeuchi Nenshi, TAKENEN, 85 NE, Takamatsu, Kahoku, Ishikawa-929-1215, Japan
| | - Satoru Takeuchi
- Factory of Takeuchi Nenshi, TAKENEN, 85 NE, Takamatsu, Kahoku, Ishikawa-929-1215, Japan
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Masciarelli S, Sitia R. Building and operating an antibody factory: redox control during B to plasma cell terminal differentiation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2008; 1783:578-88. [PMID: 18241675 DOI: 10.1016/j.bbamcr.2008.01.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2007] [Revised: 12/20/2007] [Accepted: 01/04/2008] [Indexed: 01/24/2023]
Abstract
When small B lymphocytes bind their cognate antigens in the context of suitable signals, a dramatic differentiation program is activated that leads to the formation of plasma cells. These are short-lived specialized elements, each capable of secreting several thousands antibodies per second. The massive increase in Ig synthesis and transport entails a dramatic architectural and functional metamorphosis that involves the development of the endoplasmic reticulum (ER) and secretory organelles. Massive Ig secretion poses novel metabolic requirements, particularly for what concerns aminoacid import, ATP synthesis and redox homeostasis. Ig H and L chains enter the ER in the reduced state, to be rapidly oxidised mainly via protein driven relays based on the resident enzymes PDI and Ero1. How do plasma cells cope with the ensuing metabolic and redox stresses? In this essay, we discuss the physiological implications that increased Ig production could have in the control of plasma cell generation, function and lifespan, with emphasis on the potential role of ROS generation in mitochondria and ER.
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Affiliation(s)
- Silvia Masciarelli
- Department of Biology and Technology (DiBiT), San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy.
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Dragoni S, Gori T, Lisi M, Di Stolfo G, Pautz A, Kleinert H, Parker JD. Pentaerythrityl Tetranitrate and Nitroglycerin, but not Isosorbide Mononitrate, Prevent Endothelial Dysfunction Induced by Ischemia and Reperfusion. Arterioscler Thromb Vasc Biol 2007; 27:1955-9. [PMID: 17641250 DOI: 10.1161/atvbaha.107.149278] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Short term exposure to nitroglycerin (GTN) has protective properties that are similar to ischemic preconditioning. Whether other organic nitrates such as pentaerithrityl tetranitrate (PETN) and isosorbide mononitrate (ISMN) have similar protective effects has not been explored. METHODS AND RESULTS In a randomized, parallel, double blind, controlled trial, 37 healthy young volunteers received no therapy (n=10), transdermal GTN 1.2 mg for 2 hours (n=9), PETN 80 mg (n=9), or ISMN 40 mg (n=9). Twenty-four hours later, endothelium-dependent flow-mediated vasodilation (FMD) was measured before and after local exposure to ischemia and reperfusion (IR). In the no therapy group, IR blunted FMD (FMD after IR: 1.9+/-0.6%, P<0.05), an effect that was prevented by GTN (FMD after IR: 5.3+/-1.4%, P<0.05 compared with no therapy). PETN had the same protective effect (FMD after IR: 8.1+/-1.3%, P<0.05 compared with no therapy), whereas ISMN had no significant pharmacological preconditioning effect (FMD after-IR: 3.6+/-0.8%, P=ns compared with no therapy). While it blocked the effect of GTN, Vitamin C (n=8) did not modify PETN preconditioning (FMD after IR: 6.3+/-0.9%, P=ns compared with before IR), showing that this phenomenon is not mediated by oxygen free radical production. In an effort to identify the mechanism of PETN preconditioning, isolated human endothelial cells were incubated with PETN, GTN, or ISMN. Only PETN induced expression of the genes encoding for heme oxygenase and ferritin, which have been involved in ischemic and pharmacological preconditioning. CONCLUSIONS We show important differences among organic nitrates in their capacity to prevent IR-induced endothelial dysfunction. GTN and PETN, but not ISMN, have this preconditioning effect. The potential clinical implications of these data warrant further investigation.
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Affiliation(s)
- Saverio Dragoni
- Department of Internal, Cardiovascular, and Geriatric Medicine, Azienda Ospedaliera Universitaria Senese, University of Siena, Italy
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Lee GH, Kim HK, Chae SW, Kim DS, Ha KC, Cuddy M, Kress C, Reed JC, Kim HR, Chae HJ. Bax Inhibitor-1 Regulates Endoplasmic Reticulum Stress-associated Reactive Oxygen Species and Heme Oxygenase-1 Expression. J Biol Chem 2007; 282:21618-28. [PMID: 17526500 DOI: 10.1074/jbc.m700053200] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The Bax inhibitor-1 (BI-1) is an anti-apoptotic protein that is located in endoplasmic reticulum (ER) membranes and protects cells from ER stress-induced apoptosis. The ER is associated with generation of reactive oxygen species (ROS) through oxidative protein folding. This study examined the role of BI-1 in the regulation of ER stress-induced accumulation of ROS and expression of unfolded protein response-associated proteins. BI-1 reduced the expression levels of glucose response protein 78, C/EBP homologous protein, phospho-eukaryotic initiation factor 2alpha, IRE1alpha, XBP-1, and phospho-JNK and inhibited the cleavage of ATF-6alpha p-90, leading to the inhibition of ROS. Although ROS scavengers offer some protection against ER stress-induced apoptosis, the expression of pro-apoptotic ER stress proteins was not affected. This study shows that the response of unfolded proteins is followed by ROS accumulation under ER stress, which is regulated in BI-1 cells. The mechanism for these BI-1-associated functions involves the expression of heme oxygenase-1 (HO-1) through nuclear factor erythroid 2-related factor 2. In BI-1 cells, the transfection of HO-1 small interfering RNA completely abolished the BI-1-induced protection. The endogenous expression of HO-1 through ER stress-initiated ROS is believed to be as a protection signal. In conclusion, these observations suggest that BI-1 can inhibit the ER stress proteins as well as the accumulation of ROS, thereby protecting the cells. Moreover, HO-1 plays an important role in the BI-1-associated protection against ER stress.
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Affiliation(s)
- Geum-Hwa Lee
- Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk, South Korea
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