A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.

• Klíčová slova
• cardiac, ischemia-reperfusion, remodeling, senescence, senolytic,
• MeSH
• lidé MeSH
• reperfuzní poškození metabolismus   MeSH
• stárnutí buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We tested whether treatment with exogenous L-arginine, the precursor of nitric oxide (NO), could protect the skeletal muscle from ischemia/reperfusion (I/R) injury. A rabbit hindlimb I/R model (2.5 h ischemia/2 h reperfusion) was used. Morphological changes were elucidated by morphometry. Plasma concentrations of malondialdehyde (pMDA), as well as L-arginine and L-citrulline content in the plasma and skeletal muscle were measured. I/R injury in the skeletal muscle was manifested by development of prominent interstitial edema (fraction of interfiber area was 26.23% vs 15.09% in sham operated control, p < .005) and severe microvascular constriction (capillary area was 11.41 microns2 vs 16.92 in control, p <.005). These changes were accompanied by increased pMDA levels, indicating a process of lipid peroxidation in the cell membranes. L-arginine treatment (4 mg/kg/min intravenously, for 1 h, infusion initiated 30 min before reperfusion) caused an intracellular accumulation of this amino acid in the SM. Intracellular concentrations of L-citrulline increased (201.0 mumol/dm3 after reperfusion vs 176.0 before ischemia onset, p < .005), suggesting stimulated endogenous NO synthesis. L-arginine treatment protected capillary constriction (capillary area was 17.64 microns2 vs 11.41 in the untreated animals, p < .0005) and reduced interstitial edema after reperfusion (fraction of interfiber area was 17.80% vs 26.23 in untreated animals, p < 0.005). The protective effect of L-arginine treatment on I/R injury of SM may be related to its ability to prevent microvascular constriction and reduce permeability disorders by the stimulation of endogenous NO production.

• MeSH
• arginin metabolismus   terapeutické užití   MeSH
• kosterní svaly krevní zásobení   metabolismus   patologie   MeSH
• králíci MeSH
• reperfuzní poškození farmakoterapie   metabolismus   patologie   MeSH
• zadní končetina krevní zásobení   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• arginin MeSH

OBJECTIVE: This experiment evaluated the influence of erythropoietin (Epo) in an animal model of uterine ischemia reperfusion using the quoting established protocol. DESIGN: The effects of erythropoietin treatment were evaluated by mean uterus inflammation (UI) lesions. UI lesions were determined at the 60th reperfusion min (for groups A and C) and at the 120th reperfusion min (for groups B and D). Groups A and B received no drugs, whereas rats from groups C and D were administered with erythropoietin. METHODS: 40 rats of mean mass 247.7 g were employed for the study. RESULTS: Epo administration non-significantly decreased the UI scores [without lesions] by 0.1 [-0.6244129 - 0.4244129] (p = 0.6294)). Reperfusion time kept non-significantly increased the UI scores by [without lesions] 0.15 [-0.60230385 - 0.50230385] (p = 0.5782). Together, Epo administration combined with reperfusion time non-significantly decreased the UI scores by [without lesions] 0.0727273 [-0.3886782 - 0.2432236] (p = 0.6439). CONCLUSIONS: Epo administration whether it interacted or not with reperfusion time non-significantly short-term decreased the UI lesions scores. Perhaps, a longer study time than two hours or a higher Epo dose may provide more significant effects.

• Klíčová slova
• erythropoietin, ischemia, uterus inflammation reperfusion.,
• MeSH
• antioxidancia farmakologie   MeSH
• erythropoetin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar MeSH
• reperfuzní poškození prevence a kontrola   MeSH
• uterus krevní zásobení   MeSH
• zánět farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• erythropoetin MeSH

Postnatal maturation of the heart is characterized by decreasing tolerance to ischemia/reperfusion (I/R) injury associated with significant changes in mitochondrial function. The aim of this study is to test the hypothesis that the role of the mitochondrial membrane permeability transition pore (MPTP) in the I/R injury differs in the neonatal and in the adult heart. For this purpose, the effect of blockade of MPTP on the degree of I/R injury and the sensitivity of MPTP to swelling-inducing agents was compared in hearts from neonatal (7 days old) and adult (90 days old) Wistar rats. It was found that the release of NAD(+) from the perfused heart induced by I/R can be prevented by sanglifehrin A (SfA) only in the adult myocardium; SfA had no protective effect in the neonatal heart. Furthermore, the extent of Ca-induced swelling of mitochondria from neonatal rats was significantly lower than that from the adult animals; mitochondria from neonatal rats were more resistant at higher concentrations of calcium. In addition, not only the extent but also the rate of calcium-induced swelling was about twice higher in adult than in neonatal mitochondria. The results support the idea that lower sensitivity of the neonatal MPTP to opening may be involved in the mechanism of the higher tolerance of the neonatal heart to I/R injury.

• MeSH
• krysa rodu Rattus MeSH
• laktony farmakologie   MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• přechodový pór mitochondriální permeability MeSH
• reperfuzní poškození metabolismus   MeSH
• spirosloučeniny farmakologie   MeSH
• srdeční mitochondrie metabolismus   MeSH
• transportní proteiny mitochondriální membrány metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• laktony MeSH
• přechodový pór mitochondriální permeability MeSH
• sanglifehrin A MeSH Prohlížeč
• spirosloučeniny MeSH
• transportní proteiny mitochondriální membrány MeSH

Effects of melatonin on various manifestations of ischemia/reperfusion injury of the isolated perfused rat heart were examined. Ischemia- and reperfusion-induced ventricular arrhythmias were studied under constant flow in hearts subjected to 10, 15 or 25 min of regional ischemia (induced by LAD coronary artery occlusion) and 10-min reperfusion. Melatonin was added to the perfusion medium 5 min before ischemia at concentrations of 10 micromol/l or 10 nmol/l and was present throughout the experiment. Recovery of the contractile function was evaluated under constant perfusion pressure after 20-min global ischemia followed by 40-min reperfusion. Hearts were treated with melatonin at a high concentration (10 micromol/l) either 5 min before ischemia only (M1) or 5 min before ischemia and during reperfusion (M2) or only during reperfusion (M3). At the high concentration, melatonin significantly reduced the incidence of reperfusion-induced ventricular fibrillation and decreased arrhythmia score (10% and 2.2+/-0.3, respectively) as compared with the corresponding untreated group (62% and 4.1+/-0.3, respectively); the low concentration had no effect. This substance did not affect the incidence and severity of ischemic arrhythmias. Melatonin (M2, M3) significantly improved the recovery of the contractile function as compared with the untreated group; this protection did not appear if melatonin was absent in the medium during reperfusion (Ml). Our results show that melatonin, in accordance with its potent antioxidant properties, effectively protects the rat heart against injury associated with reperfusion. It appears unlikely that melatonin is cardioprotective at physiological concentrations.

• MeSH
• fibrilace komor farmakoterapie   patofyziologie   MeSH
• ischemická choroba srdeční farmakoterapie   patofyziologie   MeSH
• komorové extrasystoly farmakoterapie   MeSH
• krysa rodu Rattus MeSH
• melatonin farmakologie   terapeutické užití   MeSH
• potkani Wistar MeSH
• reperfuzní poškození myokardu farmakoterapie   patofyziologie   MeSH
• scavengery volných radikálů farmakologie   terapeutické užití   MeSH
• srdeční arytmie farmakoterapie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• melatonin MeSH
• scavengery volných radikálů MeSH

Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles and complicate molecular diagnostics. To investigate this effect, we characterized such pre-analytical effects in 143 non-malignant liver samples obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts treated either with the Pringle manoeuvre or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-PCR. We found 179 mutually deregulated genes which point to elevated cytokine signaling with NFκB as a dominant pathway in ischemia responses. In contrast to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFκB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were present in non-tumor tissue. The reported inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a set of 230 pre-analytically highly robust genes identified from histologically normal livers (<2% covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.

• Klíčová slova
• Biomarker, Gene expression, Microarray, Pre-analytical workflows, Transplantation medicine,
• MeSH
• ischemie komplikace   metabolismus   patologie   MeSH
• játra metabolismus   MeSH
• lidé MeSH
• regulace genové exprese MeSH
• reperfuzní poškození * diagnóza   genetika   MeSH
• transkriptom * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Gastric mucus plays an important role in gastric mucosal protection. Apart from its "barrier" function, it has been demonstrated that mucus protects gastric epithelial cells against toxic oxygen metabolites derived from the xanthine/ xanthine oxidase system. In this study, we investigated the effect of malotilate and sucralfate (mucus production stimulators) and N-acetylcysteine (mucolytic agent) on ischemia/reperfusion-induced gastric mucosal injury. Gastric ischemia was induced by 30 min clamping of the coeliac artery followed by 30 min of reperfusion. The mucus content was determined by the Alcian blue method. Sucralfate (100 mg/kg), malotilate (100 mg/kg), and N-acetylcysteine (100 mg/kg) were given orally 30 min before surgery. Both sucralfate and malotilate increased the mucus production in control rats. On the other hand, N-acetyloysteine significantly decreased mucus content in control (sham) group. A significant decrease of mucus content was found in the control and the N-acetylcysteine pretreated group during the period of ischemia. On the other hand, sucralfate and malotilate prevented the decrease the content of mucus during ischemia. A similar result can be seen after ischemia/reperfusion. In the control group and N-acetylcysteine pretreated group a significant decrease of adherent mucus content was found. However, sucralfate and malotilate increased mucus production (sucralfate significantly). Sucralfate and malotilate also significantly protected the gastric mucosa against ischemia/reperfusion-induced injury. However, N-acetylcysteine significantly increased gastric mucosal injury after ischemia/reperfusion. These results suggest that gastric mucus may be involved in the protection of gastric mucosa after ischemia/reperfusion.

• MeSH
• hlen metabolismus   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• reperfuzní poškození metabolismus   MeSH
• žaludeční sliznice metabolismus   MeSH
• žaludek krevní zásobení   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The present study analyzes the effect of selective deafferentation on the reperfusion injury of the skeletal muscle when nociceptive sensory fibers of the left sciatic nerve are selectively damaged by capsaicin pretreatment in a rat model following tourniquet ischemia (ISC) applied for 30 min, 1 h, and 2 h on the left hind limb. The isometric tetanic contractile force of the extensor digitorum longus (EDL) muscle was measured after 1 h, and 1, 3, or 7 days of reperfusion. Contractile force of the damaged muscle was compared to the intact contralateral muscle. In another group, ISC was used without capsaicin pre-treatment. After 30 min of ISC, there was no difference between deafferented and non-pretreated groups. Following 1 h ISC, with the exception of 1 h reperfusion, the non-pretreated group produced stronger contractions than the deafferented group. After 2 h ISC, the contractile force of the deafferented muscle was significantly stronger compared to the non-deafferented muscle force at all reperfusion times. In conclusions, it was found that the absence of peptidergic sensory fibers after long-lasting (2 h) ischemia is beneficial in reperfusion injury, whereas the absence of vasodilator peptides has unfavorable effects if tissue damage is milder (after 1 h ischemia).

• MeSH
• denervace svalu MeSH
• isometrická kontrakce MeSH
• kapsaicin MeSH
• kosterní svaly krevní zásobení   inervace   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• neurony aferentní fyziologie   MeSH
• potkani Wistar MeSH
• reperfuzní poškození patofyziologie   MeSH
• turnikety MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kapsaicin MeSH

The aim of the study was to find out whether administration of selenium (Se) will protect the immature heart against ischemia/reperfusion.The control pregnant rats were fed laboratory diet (0.237 mg Se/kg diet); experimental rats received 2 ppm Na(2)SeO(3) in the drinking water from the first day of pregnancy until day 10 post partum. The concentration of Se in the serum and heart tissue was determined by activation analysis, the serum concentration of NO by chemiluminescence, cardiac concentration of lipofuscin-like pigment by fluorescence analysis. The 10 day-old hearts were perfused (Langendorff); recovery of developed force (DF) was measured after 40 min of global ischemia. In acute experiments, 10 day-old hearts were perfused with selenium (75 nmol/l) before or after global ischemia. Sensitivity to isoproterenol (ISO, pD(50)) was assessed as a response of DF to increasing cumulative dose.Se supplementation elevated serum concentration of Se by 16%. Se increased ischemic tolerance (recovery of DF, 32.28 +/- 2.37 vs. 41.82 +/- 2.91%, P < 0.05). Similar results were obtained after acute administration of Se during post-ischemic reperfusion (32.28 +/- 2.37 vs. 49.73 +/- 4.40%, P < 0.01). The pre-ischemic treatment, however, attenuated the recovery (23.08 +/- 3.04 vs. 32.28 +/- 2.37%, P < 0.05). Moreover, Se supplementation increased the sensitivity to the inotropic effect of ISO, decreased cardiac concentration of lipofuscin-like pigment and serum concentration of NO. Our results suggest that Se protects the immature heart against ischemia/reperfusion injury. It seems therefore, that ROS may affect the function of the neonatal heart, similarly as in adults.

• MeSH
• časové faktory MeSH
• ischemická choroba srdeční farmakoterapie   prevence a kontrola   MeSH
• kontrakce myokardu účinky léků   MeSH
• krysa rodu Rattus MeSH
• lipofuscin metabolismus   MeSH
• oxid dusnatý krev   MeSH
• perfuze MeSH
• potkani Wistar MeSH
• potravní doplňky MeSH
• reperfuzní poškození myokardu farmakoterapie   prevence a kontrola   MeSH
• selen krev   farmakologie   terapeutické užití   MeSH
• srdce účinky léků   MeSH
• těhotenství MeSH
• tělesná hmotnost účinky léků   MeSH
• velikost orgánu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• lipofuscin MeSH
• oxid dusnatý MeSH
• selen MeSH

Kupffer cells (KC), resident macrophages of the liver, have been strongly implicated in lipopolysaccharide (LPS)-induced liver graft injury. However, our recent study showed that sizofiran (schizophyllan glucan) (SPG), which activates KC, did not influence cold ischemia-reperfusion liver injury of LPS-exposed rats. Here we investigated some mechanisms by which SPG does not aggravate LPS-enhanced cold ischemia-reperfusion rat liver injury. Control and SPG-treated rats were exposed to LPS for 2 h prior to hepatectomy. The livers were cold-preserved in University of Wisconsin solution followed by reperfusion with Krebs-Henseleit buffer. We found that SPG dramatically inhibited LPS-induced increases of tumor necrosis factor-alpha (TNF-alpha) in the plasma and bile in vivo. Moreover, LPS-induced TNF- release into the washout solution after cold ischemia was also abrogated by SPG pretreatment. However, SPG increased TNF- release into the perfusate after reperfusion. On the other hand, SPG completely abolished expression of c-myc protooncogene, which is known to sensitize cells to TNF-alpha cytotoxicity. In conclusion, inhibition of both TNF- release after LPS challenge and c-myc expression may explain why activation of KC with SPG does not aggravate endotoxin-enhanced cold ischemia-reperfusion liver injury.

• MeSH
• endotoxiny toxicita   MeSH
• játra krevní zásobení   účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• nízká teplota škodlivé účinky   MeSH
• potkani Wistar MeSH
• reperfuzní poškození chemicky indukované   farmakoterapie   metabolismus   MeSH
• sizofiran farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• endotoxiny MeSH
• sizofiran MeSH