Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-α

Brief episodes of ischemia can render an organ resistant to subsequent severe ischemia. This ‘ischemic preconditioning’ is ascribed to various mechanisms, including oxidative stress. We investigated whether preconditioning exists on an endothelial level. Human umbilical vein endothelial cells (HUVECs) were transiently confronted with oxidative stress (1 mM H2O2, 5 min). Adhesion molecules ICAM-1 and E-selectin and release of cytokines IL-6 and IL-8 to subsequent stimulation with TNF-α (2.5 ng/ml, 4 h) were measured (flow cytometry and immunoassay), as were nuclear translocation of the transcription factor NFkB (Western blotting, confocal microscopy) and redox status of HUVECs (quantification of glutathione by HPLC). TNF-α elevated IL-6 in the cell supernatant from 8.8 ± 1 to 41 ± 3 pg/ml and IL-8 from 0.5 ± 0.03 to 3 ± 0.2 ng/ml. ICAM-1 was increased threefold and E-selectin rose eightfold. Oxidative stress (decrease of glutathione by 50%) reduced post-TNF-α levels of IL-6 to 14 ± 3 and IL-8 to 1 ± 0.2; the rise of ICAM-1 was completely blocked and E-selectin was only doubled. The anti-inflammatory effects of preconditioning via oxidative stress were paralleled by reduction of the translocation of NFkB on stimulation with TNF-α, and antagonized by the intracellular radical scavenger N-acetylcysteine. ‘Anti-inflammatory preconditioning’ of endothelial cells by oxidative stress may account for the inhibitory effects of preconditioning on leukocyte adhesion in vivo

The Effect of High Dose Melatonin on Cardiac Ischemia-reperfusion Injury

Purpose: Melatonin, the most potent scavenger of toxic free radicals, has been found to be effective in protecting against pathological states due to the release of reactive oxygen species. This study was performed to establish the effect of high dose melatonin on protection against ischemia-reperfusion (I/R) injury in rat hearts. Materials and Methods: Forty male Sprague-Dawley rats were used in this study. They were separated into four groups of ten rats each. A left coronary artery occlusion was induced in the rats by ligating the artery for 20 minutes and then releasing the ligation (reperfusion) afterwards. The control group was Group A. Group B was subjected to myocardial ischemia-reperfusion without any treatment, while Group C underwent myocardial ischemia-reperfusion with a melatonin treatment before the ischemia. Group D was subjected to myocardial ischemia-reperfusion with a melatonin treatment before the reperfusion. After 20 minutes of reperfusion, blood samples were obtained from each group for biochemical studies, and the animals were sacrificed for histological and, immunohistochemical examinations of the myocardial tissue. Results: We found that the cardiac troponin T(cTn-T) levels were significantly increased in Group B when all groups were compared. In the Group C rats treated with melatonin, the cTn-T values were significantly lower than those in Groups B and D. In addition, malondialdehyde (MDA) and antioxidant enzymes including, superoxide dismutase (SOD) and myeloperoxidase (MPO) were lower than those in Group B in the melatonin treated groups. The differences were statistically significant (p < 0.05). Histopathologic and immunohistopathologic studies also supported the effectiveness of melatonin. Conclusion: Our study suggests that high dose melatonin, appears to offer protection against cardiac ischemia-reperfusion injuries in rats by scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia.PURPOSE:Melatonin, the most potent scavenger of toxic free radicals, has been found to be effective in protecting against pathological states due to the release of reactive oxygen species. This study was performed to establish the effect of high dose melatonin on protection against ischemia- reperfusion (I/R) injury in rat hearts.MATERIALS AND METHODS:Forty male Sprague-Dawley rats were used in this study. They were separated into four groups of ten rats each. A left coronary artery occlusion was induced in the rats by ligating the artery for 20 minutes and then releasing the ligation (reperfusion) afterwards. The control group was Group A. Group B was subjected to myocardial ischemia-reperfusion without any treatment, while Group C underwent myocardial ischemia-reperfusion with a melatonin treatment before the ischemia. Group D was subjected to myocardial ischemia-reperfusion with a melatonin treatment before the reperfusion. After 20 minutes of reperfusion, blood samples were obtained from each group for biochemical studies, and the animals were sacrificed for histological and, immunohistochemical examinations of the myocardial tissue.RESULTS:We found that the cardiac troponin T(cTn-T) levels were significantly increased in Group B when all groups were compared. In the Group C rats treated with melatonin, the cTn-T values were significantly lower than those in Groups B and D. In addition, malondialdehyde (MDA) and antioxidant enzymes including, superoxide dismutase (SOD) and myeloperoxidase (MPO) were lower than those in Group B in the melatonin treated groups. The differences were statistically significant (p < 0.05). Histopathologic and immunohistopathologic studies also supported the effectiveness of melatonin.CONCLUSION:Our study suggests that high dose melatonin, appears to offer protection against cardiac ischemia-reperfusion injuries in rats by scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia

The Effect of High Dose Melatonin on Cardiac Ischemia-reperfusion Injury

Purpose: Melatonin, the most potent scavenger of toxic free radicals, has been found to be effective in protecting against pathological states due to the release of reactive oxygen species. This study was performed to establish the effect of high dose melatonin on protection against ischemia-reperfusion (I/R) injury in rat hearts. Materials and Methods: Forty male Sprague-Dawley rats were used in this study. They were separated into four groups of ten rats each. A left coronary artery occlusion was induced in the rats by ligating the artery for 20 minutes and then releasing the ligation (reperfusion) afterwards. The control group was Group A. Group B was subjected to myocardial ischemia-reperfusion without any treatment, while Group C underwent myocardial ischemia-reperfusion with a melatonin treatment before the ischemia. Group D was subjected to myocardial ischemia-reperfusion with a melatonin treatment before the reperfusion. After 20 minutes of reperfusion, blood samples were obtained from each group for biochemical studies, and the animals were sacrificed for histological and, immunohistochemical examinations of the myocardial tissue. Results: We found that the cardiac troponin T(cTn-T) levels were significantly increased in Group B when all groups were compared. In the Group C rats treated with melatonin, the cTn-T values were significantly lower than those in Groups B and D. In addition, malondialdehyde (MDA) and antioxidant enzymes including, superoxide dismutase (SOD) and myeloperoxidase (MPO) were lower than those in Group B in the melatonin treated groups. The differences were statistically significant (p < 0.05). Histopathologic and immunohistopathologic studies also supported the effectiveness of melatonin. Conclusion: Our study suggests that high dose melatonin, appears to offer protection against cardiac ischemia-reperfusion injuries in rats by scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia.PURPOSE:Melatonin, the most potent scavenger of toxic free radicals, has been found to be effective in protecting against pathological states due to the release of reactive oxygen species. This study was performed to establish the effect of high dose melatonin on protection against ischemia- reperfusion (I/R) injury in rat hearts.MATERIALS AND METHODS:Forty male Sprague-Dawley rats were used in this study. They were separated into four groups of ten rats each. A left coronary artery occlusion was induced in the rats by ligating the artery for 20 minutes and then releasing the ligation (reperfusion) afterwards. The control group was Group A. Group B was subjected to myocardial ischemia-reperfusion without any treatment, while Group C underwent myocardial ischemia-reperfusion with a melatonin treatment before the ischemia. Group D was subjected to myocardial ischemia-reperfusion with a melatonin treatment before the reperfusion. After 20 minutes of reperfusion, blood samples were obtained from each group for biochemical studies, and the animals were sacrificed for histological and, immunohistochemical examinations of the myocardial tissue.RESULTS:We found that the cardiac troponin T(cTn-T) levels were significantly increased in Group B when all groups were compared. In the Group C rats treated with melatonin, the cTn-T values were significantly lower than those in Groups B and D. In addition, malondialdehyde (MDA) and antioxidant enzymes including, superoxide dismutase (SOD) and myeloperoxidase (MPO) were lower than those in Group B in the melatonin treated groups. The differences were statistically significant (p < 0.05). Histopathologic and immunohistopathologic studies also supported the effectiveness of melatonin.CONCLUSION:Our study suggests that high dose melatonin, appears to offer protection against cardiac ischemia-reperfusion injuries in rats by scavenging the free radicals and could have a potential clinical use in the management of myocardial ischemia

Effects of atrial natriuretic Peptide after prolonged hypothermic storage of the isolated rat heart

Primary graft failure (PGF) caused by ischemia-reperfusion injury (IRI) is the strongest determinant of perioperative mortality after heart transplantation. Atrial natriuretic peptide (ANP) has been found to reduce the IRI of cardiomyocytes and may be beneficial in alleviating PGF after heart transplantation, although there is a lack of evidence to support this issue. The purpose of this study was to investigate the cardioprotective effects of ANP after prolonged hypothermic storage. For this purpose, an isolated working-heart rat model was used. After the preparation, the hearts were arrested with and stored in an extracellular-based cardioplegic solution at 3-4°C for 6 h and followed by 25 min of reperfusion. The hearts were divided into four groups (n = 7 in each group) according to the timing of ANP administration: Group 1 (in perfusate before storage), Group 2 (in cardioplegia), Group 3 (in reperfusate), and control (no administration of ANP). Left ventricular functional recovery and the incidence of ventricular fibrillation (VF) were compared. ANP administration at the time of reperfusion improved the percent recovery of left ventricular developed pressure (control, 45.5 ± 10.2; Group 1, 47.4 ± 8.8; Group 2, 45.3 ± 12 vs. Group 3, 76.3 ± 7; P < 0.05) and maximum first derivative of the left ventricular pressure (control, 47.9 ± 8.7; Group 1, 46.7 ± 8.8; Group 2, 49.6 ± 10.8 vs. Group 3, 76.6 ± 7.5; P < 0.05). The incidence of VF after reperfusion did not differ significantly among these four groups (71.4, 85.7, 57.1, and 85.7% in Groups 1, 2, 3, and control, respectively). This result suggests that the administration of ANP at the time of reperfusion may have the potential to decrease the incidence of PGF after heart transplantation

Transauricular embolization of the rabbit coronary artery for experimental myocardial infarction: comparison of a minimally invasive closed-chest model with open-chest surgery

<p>Abstract</p> <p>Introduction</p> <p>To date, most animal studies of myocardial ischemia have used open-chest models with direct surgical coronary artery ligation. We aimed to develop a novel, percutaneous, minimally-invasive, closed-chest model of experimental myocardial infarction (EMI) in the New Zealand White rabbit and compare it with the standard open-chest surgical model in order to minimize local and systemic side-effects of major surgery.</p> <p>Methods</p> <p>New Zealand White rabbits were handled in conformity with the "Guide for the Care and Use of Laboratory Animals" and underwent EMI under intravenous anesthesia. Group A underwent EMI with an open-chest method involving surgical tracheostomy, a mini median sternotomy incision and left anterior descending (LAD) coronary artery ligation with a plain suture, whereas Group B underwent EMI with a closed-chest method involving fluoroscopy-guided percutaneous transauricular intra-arterial access, superselective LAD catheterization and distal coronary embolization with a micro-coil. Electrocardiography (ECG), cardiac enzymes and transcatheter left ventricular end-diastolic pressure (LVEDP) measurements were recorded. Surviving animals were euthanized after 4 weeks and the hearts were harvested for Hematoxylin-eosin and Masson-trichrome staining.</p> <p>Results</p> <p>In total, 38 subjects underwent EMI with a surgical (n = 17) or endovascular (n = 21) approach. ST-segment elevation (1.90 ± 0.71 mm) occurred sharply after surgical LAD ligation compared to progressive ST elevation (2.01 ± 0.84 mm;p = 0.68) within 15-20 min after LAD micro-coil embolization. Increase of troponin and other cardiac enzymes, abnormal ischemic Q waves and LVEDP changes were recorded in both groups without any significant differences (p > 0.05). Infarct area was similar in both models (0.86 ± 0.35 cm in the surgical group vs. 0.92 ± 0.54 cm in the percutaneous group;p = 0.68).</p> <p>Conclusion</p> <p>The proposed model of transauricular coronary coil embolization avoids thoracotomy and major surgery and may be an equally reliable and reproducible platform for the experimental study of myocardial ischemia.</p

Attenuation of ischemia-reperfusion injury by ascorbic acid in the canine renal transplantation

This study examined the effects of ascorbic acid on the attenuation of an ischemia-reperfusion (I/R) injury after a canine renal transplantation. Eight beagle dogs were subjected to a renal auto-transplantation followed by the administration of ascorbic acid (treatment group) and the same amount of vehicle (physiological saline, control group). Blood samples were collected from these dogs to perform the kidney function tests and the invasive blood pressure was measured in the renal artery at pre- and post- anastomosis. The antioxidant enzymes of level 72 h after the transplant were measured. The kidneys were taken for a histopathology evaluation at day 21. The kidney function tests showed a significant difference between the control and treatment group. The invasive blood pressure in the renal artery was similar in the groups. The activity of the antioxidant enzymes in the blood plasma was significant lower in the control group than in the treatment group. The histopathology findings revealed the treatment group to have less damage than the control group. The results of this study suggest that ascorbic acid alone might play a role in attenuating I/R injury and assist in the recovery of the renal function in a renal transplantation model

'Open Marxism' against and beyond the 'Great Enclosure'? Reflections on How (Not) to Crack Capitalism

The main purpose of this article is to provide an in-depth discussion of John Holloway’s recent book, Crack Capitalism. To this end, the paper offers a detailed account of the key strengths and weaknesses of Holloway’s version of ‘open Marxism’. The analysis is divided into two parts. The first part focuses on six significant strengths of Crack Capitalism: (1) its insistence upon the importance of autonomous forms of agenda-setting for both individual and collective emancipation; (2) its emphasis on the ordinary constitution of social struggles; (3) its fine-grained interpretation of the socio-ontological conditions underlying human agency; (4) its processual conception of radical social transformation; (5) its recognition of the elastic, adaptable, and integrative power of capitalism; and (6) its proposal for an alternative critical theory, commonly known as ‘open Marxism’ or ‘autonomous Marxism’. The second part of the study examines the principal weaknesses of Crack Capitalism: (1) the counterproductive implications of the preponderance of negativity, owing to a one-sided concern with critique, cracks, and crises; (2) conceptual vagueness; (3) an overuse of poetic and metaphorical language; (4) the absence of a serious engagement with the question of normativity; (5) a lack of substantive evidence; (6) a residual economic reductionism; (7) a simplistic notion of gender; (8) the continuing presence of various problematic ‘isms’; (9) the misleading distinction between ‘doing’ and ‘labour’; (10) a reductive understanding of capitalism; (11) an unrealistic view of society; and (12) socio-ontological idealis

Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

Publisher Copyright: © 2014 The British Pharmacological Society.Background and Purpose The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury. Key Results In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg-1) decreased the infarct size by 45-48%. In vivo pretreatment with Methyl-GBB (20 mg·kg-1) attenuated the infarct size by 45% and improved 24 h survival of rats by 20-30%. Conclusions and Implications Reduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia-reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism.publishersversionPeer reviewe