Anti-IL-20 Antibody Protects against Ischemia/Reperfusion-Impaired Myocardial Function through Modulation of Oxidative Injuries, Inflammation and Cardiac Remodeling

Acute myocardial infarction (AMI) is the most critical event in the disease spectrum of coronary artery disease. To rescue cardiomyocytes in AMI, it is important to restore blood supply as soon as possible to reduce ischemia-induced injury. However, worse damage can occur during the reperfusion phase, called the reperfusion injury. Under ischemia/reperfusion (I/R) injury, elevated oxidative stress plays a critical role in regulation of apoptosis, inflammation and remodeling of myocardium. Our previous study has demonstrated that interleukin (IL)-20 is increased during hypoxia/reoxygenation stimulation and promotes apoptosis in cardiomyocytes. This study was, therefore, designed to investigate whether IL-20 antibody could reduce I/R-induced myocardial dysfunction. Results from this study revealed that IL-20 antibody treatment significantly suppressed I/R-induced nicotinamide adenine dinucleotide phosphate oxidase, oxidative stress, apoptosis, proinflammatory responses, cardiac fibrosis, and expression of cardiac remodeling markers in Sprague-Dawley rats. Plasma B-type natriuretic peptide level was also reduced by IL-20 antibody injection. IL-20 antibody treatment appeared to restore cardiac function under the I/R injury in terms of greater values of ejection fraction and fractional shortening compared to the control group. Two commonly used indicators of cardiac injury, lactate dehydrogenase and creatine kinase-MB, were also lower in the IL-20 antibody injection group. Taken together, our results suggested that IL-20 antibody holds the potential to reduce the I/R-elicited cardiac dysfunction by preventing cardiac remodeling.

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Interplay of Oxidative Stress and Necrosis-like Cell Death in Cardiac Ischemia/Reperfusion Injury: A Focus on Necroptosis

Biomedicines ◽

10.3390/biomedicines10010127 ◽

2022 ◽

Vol 10 (1) ◽

pp. 127

Author(s):

Adriana Adameova ◽

Csaba Horvath ◽

Safa Abdul-Ghani ◽

Zoltan V. Varga ◽

M. Saadeh Suleiman ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Critical Role ◽

Research Work ◽

Ischemic Heart ◽

Phosphoglycerate Mutase ◽

Regulated Necrosis ◽

Cell Death Program

Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and post-infarction heart failure (HF). Accordingly, it has been documented that the modulation of key molecules of the canonical signaling pathway of necroptosis, involving receptor-interacting protein kinases (RIP1 and RIP3) as well as mixed lineage kinase domain-like pseudokinase (MLKL), elicit cardioprotective effects. This is evidenced by the reduction of the MI-induced infarct size, alleviation of myocardial dysfunction, and adverse cardiac remodeling. In addition to this molecular signaling of necroptosis, the non-canonical pathway, involving Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of mitochondrial permeability transition pore (mPTP) opening, and phosphoglycerate mutase 5 (PGAM5)–dynamin-related protein 1 (Drp-1)-induced mitochondrial fission, has recently been linked to ischemic heart injury. Since MI and HF are characterized by an imbalance between reactive oxygen species production and degradation as well as the occurrence of necroptosis in the heart, it is likely that oxidative stress (OS) may be involved in the mechanisms of this cell death program for inducing cardiac damage. In this review, therefore, several observations from different studies are presented to support this paradigm linking cardiac OS, the canonical and non-canonical pathways of necroptosis, and ischemia-induced injury. It is concluded that a multiple therapeutic approach targeting some specific changes in OS and necroptosis may be beneficial in improving the treatment of ischemic heart disease.

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LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

Current Neurovascular Research ◽

10.2174/1567202617666200727142019 ◽

2020 ◽

Vol 17 (4) ◽

pp. 394-401

Author(s):

Yuanhua Wu ◽

Yuan Huang ◽

Jing Cai ◽

Donglan Zhang ◽

Shixi Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Ischemia Reperfusion ◽

Critical Role ◽

Cell Activity ◽

Ht22 Cells ◽

Cerebral Ischemic ◽

Cerebral Ischemic Reperfusion ◽

And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

2021 ◽

Vol 10 (6) ◽

pp. 931

Author(s):

Anureet K. Shah ◽

Sukhwinder K. Bhullar ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Hypertrophied Heart ◽

Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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Remote Ischemic Preconditioning Protects Against Endothelial Dysfunction in a Human Model of Systemic Inflammation: A Randomized Clinical Trial

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316388 ◽

2021 ◽

Author(s):

Marco Orlandi ◽

Stefano Masi ◽

Devina Bhowruth ◽

Yago Leira ◽

Georgios Georgiopoulos ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Systemic Inflammation ◽

Ischemic Preconditioning ◽

Ischemia Reperfusion ◽

Remote Ischemic Preconditioning ◽

Human Model ◽

Control Group ◽

Flow Mediated Dilatation ◽

And Oxidative Stress

Objective: Inflammation, oxidative stress, and endothelial dysfunction are known to contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) protects from endothelial dysfunction and the damage induced by ischemia-reperfusion. Using intensive periodontal treatment (IPT), an established human model of acute systemic inflammation, we investigated whether RIPC prevents endothelial dysfunction and modulates systemic levels of inflammation and oxidative stress. Approach and Results: Forty-nine participants with periodontitis were randomly allocated to receive either 3 cycles of ischemia-reperfusion on the upper limb (N=25, RIPC) or a sham procedure (N=24, control) before IPT. Endothelial function assessed by flow-mediated dilatation of the brachial artery, inflammatory cytokines, markers of vascular injury, and oxidative stress were evaluated at baseline, day 1, and day 7 after IPT. Twenty-four hours post-IPT, the RIPC group had lower levels of IL (interleukin)-10 and IL-12 compared with the control group ( P <0.05). RIPC attenuated the IPT-induced increase in IL-1β, E-selectin, sICAM-3 (soluble intercellular adhesion molecule 3), and s-thrombomodulin levels between the baseline and day 1 ( P for interaction <0.1). Conversely, oxidative stress was differentially increased at day1 in the RIPC group compared with the control group ( P for interaction <0.1). This was accompanied by a better flow-mediated dilatation (mean difference 1.75% [95% CI, 0.428–3.07], P =0.011). After 7 days from IPT, most of the inflammatory markers endothelial-dependent and -independent vasodilation were similar between groups. Conclusions: RIPC prevented acute endothelial dysfunction by modulation of inflammation and oxidation processes in patients with periodontitis following exposure to an acute inflammatory stimulus. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03072342.

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Local anesthetic Ropivacaine protects rats from myocardial ischemia/reperfusion injury by inhibition of COX-2

Archives of Medical Science ◽

10.5114/aoms/132472 ◽

2021 ◽

Author(s):

Zhou Yu ◽

Sufang Sun ◽

Fang Hu

Keyword(s):

Oxidative Stress ◽

Creatine Kinase ◽

Ischemia Reperfusion ◽

Inos Expression ◽

Ischaemic Injury ◽

Cardiac Tissues ◽

Tnf Α ◽

Creatine Kinase Mb ◽

Cellular Apoptosis ◽

Cox 2

IntroductionMyocardial ischaemia/reperfusion (I/R) injury is the leading cause of morbidity and mortality worldwide. Despite novel advances in therapeutics, the management of myocardial I/R is still an unmet medical need. Therefore, in the present study, we have demonstrated the protective effect of ropivacaine (RPC) on the myocardial infarction in rats and its underlying mechanism.Material and methodsInitially, the effect of RPC was determined on the infarct size and histopathology of cardiac tissues. The effect of RPC was also determined on the levels of various cardiac biomarkers such as creatine kinase (CK), creatine kinase MB (CK-MB), alanine aminotransferase (ALT), asparganine aminotransferase (AST), and lactate dehydrogenase (LDH), and biomarkers of oxidative stress (MDA, SOD, and GSH) and inflammation (tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and IL-6). RPC effect was also quantified on cellular apoptosis and COX-2 and iNOS expression via western blot analysis. The RPC was further docked into the active site of COX-2.ResultsIt has been found that RPC reduces the improves haemodynamics of (LVSP and ± dp/dtmax, and LVEDP), infarct percentage and architecture of cardiac tissues of rats. It also reduces the level of studies cardiac injury biomarkers together with a reduction of oxidative stress (MDA, SOD, and GSH) and inflammation (TNF-α, IL-1β, and IL-6). Upon administration of RPC, the rate of cellular apoptosis was found to be greatly reduced, with a reduction in COX-2 and iNOS expression. In docking analysis, RPC creates van der Waals forces and pi-interactions with Tyr381, Arg106, Val102, Leu345, Val509, Ser339, Leu338, Val335, Ala513, His75, and Leu517 at the catalytic site of COX-2.ConclusionsCollectively, our results demonstrated that ropivacaine showed significant benefit against myocardial ischaemic injury.

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Ascorbic acid improves renal microcirculatory oxygenation in a rat model of renal I/R injury

Journal of Translational Internal Medicine ◽

10.1515/jtim-2015-0011 ◽

2015 ◽

Vol 3 (3) ◽

pp. 116-125 ◽

Cited By ~ 3

Author(s):

Bulent Ergin ◽

Coert J. Zuurbier ◽

Rick Bezemer ◽

Asli Kandil ◽

Emre Almac ◽

...

Keyword(s):

Oxidative Stress ◽

Ascorbic Acid ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Tissue ◽

Control Group ◽

Free Oxygen Radicals ◽

Time Control ◽

Inflammatory Parameters

AbstractBackground and objectives: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. Materials and methods: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. Results: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. Conclusion: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.

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Neuroprotective effect of a new free radical scavenger HL-008 against ischemia-reperfusion injury

10.21203/rs.3.rs-123994/v1 ◽

2020 ◽

Author(s):

Yahong Liu ◽

Ying Cheng ◽

Wei Zhang ◽

Hongqi Tian

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Brain Tissue ◽

Cell Activation ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Critical Role ◽

Radical Scavenger

Abstract Oxidative stress plays a critical role in cerebral ischemia-reperfusion injury. We previously developed a powerful antioxidant, HL-008, and this study aimed to investigate the neuroprotective function of HL-008. The in vitro and in vivo efficacy of HL-008 was evaluated using a PC-12 cell oxidative stress model induced by hydrogen peroxide and a rat model of middle cerebral artery occlusion, respectively. The MTT assay was used to analyze cell viability. TTC staining, HE staining, immunofluorescence, western blot, and proteomics were used to evaluate the infarction volume, brain tissue morphology, apoptosis, inflammation, and related pathways. Indicators related to oxidative levels were mainly detected using commercial kits. HL-008 significantly reduced the cerebral infarction area induced by ischemia-reperfusion, improved the neurological score, alleviated oxidative stress and inflammation in the brain tissue, reduced glial cell activation, inhibited brain tissue apoptosis by influencing multiple signaling pathways, and had a neuroprotective effect. If HL-008 is successfully developed, it can significantly improve the quality of life of stroke patients.

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The influence of Theranekron® on glucose-6-phosphate dehydrogenase activity in rat ovaries, intact and with ischemia-reperfusion injury

Veterinarski arhiv ◽

10.24099/vet.arhiv.0828 ◽

2021 ◽

Vol 91 (1) ◽

pp. 81-88

Author(s):

Tolunay Kozlu ◽

◽

Fatma Güler ◽

Pınar Peker Akalın ◽

Filiz Kazak ◽

...

Keyword(s):

Reperfusion Injury ◽

Dehydrogenase Activity ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Control Group ◽

Group 4 ◽

Group 3 ◽

Group 2 ◽

Glucose 6 Phosphate Dehydrogenase

The effect of Theranekron® on rat ovaries was evaluated in healthy and ischemia-reperfusion injury models. The rats were divided into four groups: group 1: control, group 2: Theranekron® (single dose of 0.3 mg/kg intraperitoneally), group 3: torsion + detorsion, and group 4: torsion + detorsion + Theranekron® (single dose 0,3 mg/kg, intraperitoneally). The ovaries were homogenized by sonication before the analysis and supernatant glucose-6-phosphate dehydrogenase activity, reduced nicotinamide adenine dinucleotide phosphate, reduced glutathione and total protein levels were evaluated spectrophotometrically. Ovary tissues were histologically examined. In group 2, glucose-6-phosphate dehydrogenase activity was significantly reduced (P<0.01) compared to the control group and an increased number of atretic follicles, and hyperaemic and haemorrhagic regions were seen histologically; in group 3, although glucose-6-phosphate dehydrogenase activity was not changed, intense hyperaemia and hemorrhage was observed in the veins of the medulla region and in the cortex. Group 4 showed a decrease in glucose-6-phosphate dehydrogenase activity compared to the control group (P<0.01). Histologically, when compared to group 3, group 4 showed fewer atretic follicles and decreased hyperaemia and hemorrhage in the ovaries, excluding the medulla region. There were no significant differences regarding reduced glutathione and reduced nicotinamide adenine dinucleotide phosphate levels between the groups. The Theranekron® dose applied had some negative effects, such as reduced glucose-6-phosphate dehydrogenase activity, an increased number of atretic follicles, and hyperemia in the corpus luteum and medulla region in intact rat ovaries. Although it reduced glucose-6-phosphate dehydrogenase activity, Theranekron® may have had slight remedial effects on rat ovaries with ischemia-reperfusion injury.

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Protective effects of bisoprolol against cadmium-induced myocardial toxicity through inhibition of oxidative stress and NF-κΒ signalling in rats

Journal of Veterinary Research ◽

10.2478/jvetres-2021-0054 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Jinhua Liu ◽

Ying Xie ◽

Zhujun Han ◽

Hailong Wang ◽

Wenhu Xu

Keyword(s):

Oxidative Stress ◽

Cardiac Injury ◽

Therapeutic Drug ◽

Control Group ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tissue Samples ◽

Gum Acacia ◽

Tnf Α ◽

Creatine Kinase Mb

Abstract Introduction The aim of the study was to investigate the mitigative effects of bisoprolol (BIS) in cadmium-induced myocardial toxicity on oxidative stress and its inhibitive effect on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling in rats. Material and Methods Male albino Wistar rats were assigned to control, Cd, BIS 2 (2 mg/kg b.w.) and BIS 8 (8 mg/kg b.w.) groups with nine rats in each. Over four weeks, the control group was administered 1% gum acacia, all other groups received 3mg/kg b.w. CdCl2 dissolved in distilled water, and the BIS groups were additionally given bisoprolol in gum acacia. Blood samples were collected for biochemical estimations. Blood pressure and serum biomarker (lactate dehydrogenase, aspirate transaminase, alanine transferase and creatine kinase-MB, enzyme (superoxide dismutase, lipid hydroxy peroxidase, catalase and malondialdehyde), and tumour necrosis factor alpha (TNF-α) concentrations were measured. Western blot analysis was conducted for NF-κB and glutathione S-transferase (GST). After sacrificing the rats, cardiac tissue samples were examined histopathologically. Results Our findings pointed to a significant decrease (P < 0.05) in the studied serum biomarkers and levels of the relevant enzymes in the BIS 8 group compared to the Cd group. A significant decrease (P < 0.05) in NF-kB p65 expression and TNF-α levels was noted in the BIS 8 group relative to the BIS 2 and Cd groups, indicating a reduction at a higher dose. In microscopy, histopathological changes in the cardiac muscles of the BIS 8 group were evident compared to those of the Cd group. Conclusion BIS seemed to have protective effects against cardiac injury induced by cadmium and could be considered a novel therapeutic drug and prognostic biomarker in the pathology of the many cardiovascular diseases caused by heavy metal intake.

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A Pilot Study of Matrix Metalloproteinases on the Model of Daunorubicin-induced Cardiomyopathy in Rabbits

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2017.65 ◽

2007 ◽

Vol 50 (2) ◽

pp. 109-111 ◽

Cited By ~ 1

Author(s):

Anna Potáčová ◽

Michaela Adamcová ◽

Martin Štěrba ◽

Olga Popelová ◽

Tomáš Šimůnek ◽

...

Keyword(s):

Oxidative Stress ◽

Matrix Metalloproteinases ◽

Cardiac Remodeling ◽

Cardiac Troponin ◽

Troponin T ◽

Myocardial Necrosis ◽

Control Group ◽

Cardiac Troponin T ◽

Wet Weight

Matrix metalloproteinases (MMPs), activated by oxidative stress, play a key role during cardiac remodeling. In the present study we aimed to assess the role of MMPs in experimental cardiomyopathy induced by repeated 10-week administration of daunorubicin (3 mg/kg i.v.) to rabbits. In the daunorubicin group, the plasma cardiac troponin T levels (cTnT – a marker of myocardial necrosis) were significantly increased (p<0.05), commencing with the 8th administration compared with the controls. The amount of collagen (an estimate of fibrosis) was also significantly higher in the daunorubicin group (13.39 ± 0.97 mg/g wet weight) compared to the control group (10.03 ± 0.65 mg/g wet weight). In both groups, the LV MMP-activity was observed only in the gelatine substrate in the 70 kDa region (MMP-2), while no MMPs activities were detectable either in the casein or collagen containing zymograms. At the end of the experiment, the MMP- 2 activity was slightly up-regulated (by 16 %) compared with the controls.

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