scholarly journals Cardioprotective Effects of PPARβ/δ Activation against Ischemia/Reperfusion Injury in Rat Heart Are Associated with ALDH2 Upregulation, Amelioration of Oxidative Stress and Preservation of Mitochondrial Energy Production

2021 ◽  
Vol 22 (12) ◽  
pp. 6399
Author(s):  
Ioanna Papatheodorou ◽  
Eleftheria Galatou ◽  
Georgios-Dimitrios Panagiotidis ◽  
Táňa Ravingerová ◽  
Antigone Lazou
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Energy Production ◽  
Citrate Synthase ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Isocitrate Dehydrogenase 2

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARβ/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARβ/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARβ/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARβ/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARβ/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARβ/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.

scholarly journals The effect of a physiological increase in temperature on mitochondrial fatty acid oxidation in rat myofibers

2019 ◽  
Vol 127 (2) ◽  
pp. 312-319 ◽  
Author(s):  
Pierre-Emmanuel Tardo-Dino ◽  
Julianne Touron ◽  
Stéphane Baugé ◽  
Stéphanie Bourdon ◽  
Nathalie Koulmann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Citrate Synthase ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Carbohydrate Oxidation ◽  
Effect Of Temperature ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Mitochondrial Efficiency

We investigated the effect of temperature increase on mitochondrial fatty acid (FA) and carbohydrate oxidation in the slow-oxidative skeletal muscles (soleus) of rats. We measured mitochondrial respiration at 35°C and 40°C with the physiological substrates pyruvate + 4 mM malate (Pyr) and palmitoyl-CoA (PCoA) + 0.5 mM malate + 2 mM carnitine in permeabilized myofibers under nonphosphorylating ([Formula: see text]) or phosphorylating ([Formula: see text]) conditions. Mitochondrial efficiency was calculated by the respiratory control ratio (RCR = [Formula: see text]/[Formula: see text]). We used guanosine triphosphate (GTP), an inhibitor of uncoupling protein (UCP), to study the mechanisms responsible for alterations of mitochondrial efficiency. We measured hydrogen peroxide (H2O2) production under nonphosphorylating and phosphorylating conditions at both temperatures and substrates. We studied citrate synthase (CS) and 3-hydroxyl acyl coenzyme A dehydrogenase (3-HAD) activities at both temperatures. Elevating the temperature from 35°C to 40°C increased PCoA-[Formula: see text] and decreased PCoA-RCR, corresponding to the uncoupling of oxidative phosphorylation (OXPHOS). GTP blocked the heat-induced increase of PCoA-[Formula: see text]. Rising temperature moved toward a Pyr-[Formula: see text] increase, without significance. Heat did not alter H2O2 production, resulting from either PCoA or Pyr oxidation. Heat induced an increase in 3-HAD but not in CS activities. In conclusion, heat induced OXPHOS uncoupling for PCoA oxidation, which was at least partially mediated by UCP and independent of oxidative stress. The classically described heat-induced glucose shift may actually be mostly due to a less efficient FA oxidation. These findings raise questions concerning the consequences of heat-induced alterations in mitochondrial efficiency of FA metabolism on thermoregulation. NEW & NOTEWORTHY Ex vivo exposure of skeletal myofibers to heat uncouples substrate oxidation from ADP phosphorylation, decreasing the efficiency of mitochondria to produce ATP. This heat effect alters fatty acids (FAs) more than carbohydrate oxidation. Alteration of FA oxidation involves uncoupling proteins without inducing oxidative stress. This alteration in lipid metabolism may underlie the preferential use of carbohydrates in the heat and could decrease aerobic endurance.

scholarly journals Mixture of MMP-2, MLC, and NOS Inhibitors Affects NO Metabolism and Protects Heart from Cardiac I/R Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Anna Krzywonos-Zawadzka ◽  
Aleksandra Franczak ◽  
Grzegorz Sawicki ◽  
Iwona Bil-Lula
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Tissue Expression ◽  
Matrix Metalloproteinase 2 ◽  
No Production ◽  
Nos Inhibitors

Objectives. Coronary reperfusion procedure leads to ischemia/reperfusion injury of the heart (IRI). IRI arises from increased degradation of myosin light chains and increased activity of matrix metalloproteinase 2 (MMP-2). Increased production of toxic peroxynitrite (ONOO−) during oxidative stress is a source of increased nitration/nitrosylation of contractile proteins, which enhance their degradation through MMP-2. Hence, an imbalance in nitric oxide (NO) metabolism along with oxidative stress is an important factor contributing to pathophysiology of cardiovascular disorders, including myocardial infarction. The aim of the current study was to provide an important insight into understanding the interaction of iNOS, eNOS, and ADMA during oxidative stress and to propose the beneficial therapy to modulate this interaction. Material and Methods. Pathogen-free Wistar rats were used in this study as a surrogate heart model ex vivo. Rat hearts perfused using the Langendorff method were subjected to global no-flow ischemia with or without administration of DOXY (1 µM), ML-7 (0.5 µM), and L-NAME (2 µM) mixture. Haemodynamic parameters of heart function, markers of I/R injury, tissue expression of iNOS, eNOS, and phospho-eNOS, asymmetric dimethylarginine, and NO production as well as MMP-2 activity were measured. Results. Mechanical heart function and coronary flow (CF) were decreased in the hearts subjected to I/R. Treatment of the hearts with the tested mixture resulted in a recovery of mechanical function due to decreased activity of MMP‐2. An infusion of Doxy, ML-7, and L-NAME mixture into I/R hearts decreased the expression of iNOS, eNOS, and phospho-eNOS and in consequence reduced ADMA expression. Decreased ADMA production led to enhanced NO synthesis and improvement of cardiac function at 85% of aerobic control. Conclusions. Synergistic effect of the multidrug therapy with the subthreshold doses allows addressing a few pathways of I/R injury simultaneously to achieve protection of cardiac function during I/R.

scholarly journals Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury from Oxidative Stress by Regulating Succinate, Lysophospholipid Metabolism, and ROS Scavenging System

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Miaomiao Jiang ◽  
Jingyu Ni ◽  
Yuanlin Cao ◽  
Xiaoxue Xing ◽  
Qian Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Heme Oxygenase 1 ◽  
Ros Scavenging ◽  
Astragaloside Iv ◽  
Wide Range

Astragaloside IV is one of the main active ingredients isolated from Astragalus membranaceus. Here we confirmed its protective effect against cardiac ischemia-reperfusion (I/R) injury and aimed to investigate the potential molecular mechanisms involved. Pretreatment of ex vivo and in vivo I/R-induced rat models by astragaloside IV significantly prevented the ratio of myocardium infarct size, systolic and diastolic dysfunction, and the production of creatine kinase and lactate dehydrogenase. Metabolic analyses showed that I/R injury caused a notable reduction of succinate and elevation of lysophospholipids, indicating excessive reactive oxygen species (ROS) generation driven by succinate’s rapid reoxidization and glycerophospholipid degradation. Molecular validation mechanistically revealed that astragaloside IV stimulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) released from Kelch-like ECH-associated protein 1 (Keap1) and translocated to the nucleus to combine with musculoaponeurotic fibrosarcoma (Maf) to initiate the transcription of antioxidative gene heme oxygenase-1 (HO-1), which performed a wide range of ROS scavenging processes against pathological oxidative stress in the hearts. As expected, increasing succinate and decreasing lysophospholipid levels were observed in the astragaloside IV-pretreated group compared with the I/R model group. These results suggested that astragaloside IV ameliorated myocardial I/R injury by modulating succinate and lysophospholipid metabolism and scavenging ROS via the Nrf2 signal pathway.

scholarly journals Cardiac mTOR protects the heart against ischemia-reperfusion injury

2012 ◽  
Vol 303 (1) ◽  
pp. H75-H85 ◽  
Author(s):  
Toshinori Aoyagi ◽  
Yoichiro Kusakari ◽  
Chun-Yang Xiao ◽  
Brendan T. Inouye ◽  
Masaya Takahashi ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ex Vivo ◽  
Left Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower in mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

2008 ◽  
Vol 294 (3) ◽  
pp. H1291-H1297 ◽  
Author(s):  
Ruiping Huang ◽  
Amrita Karve ◽  
Ibrahim Shah ◽  
Mark C. Bowers ◽  
Donald J. DiPette ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Creatine Kinase ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Calcitonin Gene Related Peptide ◽  
Left Ventricular ◽  
Sensory Nerves ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and Aδ-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the α-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from α-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the α-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the α-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of α-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress.

scholarly journals Lebetin 2, a Snake Venom-Derived B-Type Natriuretic Peptide, Provides Immediate and Prolonged Protection against Myocardial Ischemia-Reperfusion Injury via Modulation of Post-Ischemic Inflammatory Response

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 524 ◽  
Author(s):  
Bochra Tourki ◽  
Anais Dumesnil ◽  
Elise Belaidi ◽  
Slim Ghrir ◽  
Diane Godin-Ribuot ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Inflammatory Response ◽  
Natriuretic Peptide ◽  
Snake Venom ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
M1 Macrophage ◽  
Myocardial Ischemia Reperfusion

Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, including post-MI inflammation and fibrosis have not been defined. Here, we determined whether a single L2 injection exerts cardioprotection in IR murine models in vivo, and whether inflammatory response to ischemic injury plays a role in L2-induced effects. We quantified infarct size (IS), fibrosis, inflammation, and both endothelial cell and cardiomyocyte densities in injured myocardium and compared these values with those induced by B-type natriuretic peptide (BNP). Both L2 and BNP reduced IS, fibrosis, and inflammatory response after IR, as evidenced by decreased leukocyte and proinflammatory M1 macrophage infiltrations in the infarcted area compared to untreated animals. However, only L2 increased anti-inflammatory M2-like macrophages. L2 also induced a higher density of endothelial cells and cardiomyocytes. Our data show that L2 has strong, acute, prolonged cardioprotective effects in post-MI that are mediated, at least in part, by the modulation of the post-ischemic inflammatory response and especially, by the enhancement of M2-like macrophages, thus reducing IR-induced necrotic and fibrotic effects.

scholarly journals Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Raffaella Mastrocola ◽  
Claudia Penna ◽  
Francesca Tullio ◽  
Saveria Femminò ◽  
Debora Nigro ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Protective Effects ◽  
Risk Pathway ◽  
Lactate Dehydrogenase Release ◽  
Pyrin Domain

Although the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome has been recently detected in the heart, its role in cardiac ischemia/reperfusion (IR) is still controversial. Here, we investigate whether a pharmacological modulation of NLRP3 inflammasome exerted protective effects in an ex vivo model of IR injury. Isolated hearts from male Wistar rats (5-6 months old) underwent ischemia (30 min) followed by reperfusion (20 or 60 min) with and without pretreatment with the recently synthetized NLRP3 inflammasome inhibitor INF4E (50 μM, 20 min before ischemia). INF4E exerted protection against myocardial IR, shown by a significant reduction in infarct size and lactate dehydrogenase release and improvement in postischemic left ventricular pressure. The formation of the NLRP3 inflammasome complex was induced by myocardial IR and attenuated by INF4E in a time-dependent way. Interestingly, the hearts of the INF4E-pretreated animals displayed a marked improvement of the protective RISK pathway and this effect was associated increase in expression of markers of mitochondrial oxidative phosphorylation. Our results demonstrate for the first time that INF4E protected against the IR-induced myocardial injury and dysfunction, by a mechanism that involves inhibition of the NLRP3 inflammasome, resulting in the activation of the prosurvival RISK pathway and improvement in mitochondrial function.

Pomegranate extract ameliorates renal ischemia/reperfusion injury in rats via suppressing NF-κB pathway

2021 ◽  
pp. 096032712110419
Author(s):  
Mirhan N Makled ◽  
Mohammed S El-Awady ◽  
Rania R Abdel-Aziz ◽  
Ahmed B Shehab El-Din ◽  
Elsayed M Ammar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Myeloperoxidase Activity ◽  
Inhibitory Protein ◽  
And Oxidative Stress

Inflammation and oxidative stress are the major pathways involved in ischemia–reperfusion (I/R)-induced renal injury. This study was designed to evaluate the potential effect of pomegranate against I/R-induced renal injury. I/R injury was induced in nephrectomized rats by unilateral occlusion of the left renal pedicle for 45 min followed by 24 h of perfusion. Pomegranate succeeded to decrease serum levels of creatinine, potassium, and urea nitrogen, along with increasing creatinine clearance. Pomegranate also decreased I/R-induced changes in histopathological examination. Pomegranate attenuated the renal inflammatory response reflected by the suppression of nuclear factor κB p65 DNA binding activity, the upregulation of inhibitory protein kappa B-alpha mRNA expression, the downregulation of mRNA and protein expression of tumor necrosis factor α, in addition to the reduced myeloperoxidase activity and mRNA expression. Additionally, pomegranate attenuated oxidative stress likely through the modulation of lipid peroxidation and antioxidant levels reflected by the decreased MDA content and the increased glutathione level and superoxide dismutase activity. Results confirm the potential protective effect of pomegranate against I/R-induced renal injury through its anti-inflammatory and anti-oxidant effects mediated through the upregulation of inhibitory protein kappa B-alpha, the inhibition of NF-κB activity, and the associated TNF-α release, neutrophil infiltration, and oxidative stress.

Abstract 2487: Ischemia/Reperfusion Injury Impairs Myogenic Tone of Cerebral Vessels in both Ischemic and Nonischemic Hemispheres: Differential Role of Oxidative Stress.

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Maha Coucha ◽  
Weiguo Li ◽  
Adviye Ergul
Keyword(s):  
Oxidative Stress ◽  
Wistar Rats ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cerebral Arteries ◽  
Glucose Deprivation ◽  
Myogenic Tone ◽  
Ex Vivo Model

Cerebrovascular autoregulation and reactivity are critical to maintain constant perfusion during ischemic brain injury. It is known that ischemia/ reperfusion (I/R) injury and resulting oxidative stress impair vessel reactivity in ischemic hemisphere. Yet the behavior of vessels in nonischemic hemisphere is still unexplored. Hypothesis: I/R injury impairs myogenic tone of vessels in both ischemic and nonischemic hemispheres via increased peroxynitrite (ONOO - ) generation. Methods: Middle cerebral arteries (MCA) isolated from age matched male Wistar rats (n=6) subjected to 30 min MCA occlusion (MCAO)/45 min reperfusion, or MCAO followed by treatment with ONOO - scavenger FeTPPs (20mg/kg) at reperfusion were pressurized in arteriograph chamber. In another set of animals, MCA isolated from control Wistar rats were exposed to ex vivo oxygen-glucose deprivation (OGD) then their myogenic tones across the pressure range were determined. Results: I/R injury impaired myogenic tone of vessels in both ischemic and nonischemic sides albeit to a different degree. Interestingly FeTPPs restored myogenic tone of vessels from ischemic side only ( Table ). Vessels exposed to ex vivo and in vivo hypoxia experienced loss of myogenic tone. The reduction of myogenic tone % by OGD is similar to I/R injury. Conclusion: Our ex vivo model of hypoxia is a valuable method to assess the ischemic insult on vessel reactivity. Increased ONOO - production is one of the underlying mechanisms of loss of tone under I/R injury in ischemic hemisphere, but the impairment of myogenic tone in nonischemic hemisphere involves other mechanisms. Understanding how I/R alters myogenic tone and ultimately cerebral perfusion in both ischemic and nonischemic hemispheres is vital in improving current preventive and therapeutic strategies for acute stroke. + p<0.001, * p< 0.05 vs Sham, # p<0.001 vs ischemic MCA , ** p<0.01 vs nonischemic MCA

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