Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats.
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SUBMITTER: Seefeldt JM
PROVIDER: S-EPMC8100147 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAlthough early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress.ObjectivesThis study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes.MethodsA left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro-single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro-computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken.ResultsMyocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72-treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72-treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits.ConclusionsSingle-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia-reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.
| S-EPMC5659834 | biostudies-literature
Project description:Quercetin, a polyphenolic compound existing in many vegetables, fruits, has antiinflammatory, antiproliferation, and antioxidant effect on mammalian cells. Quercetin was evaluated for protecting cardiomyocytes from ischemia/reperfusion injury, but its protective mechanism remains unclear in the current study. The cardioprotective effects of quercetin are achieved by reducing the activity of Src kinase, signal transducer and activator of transcription 3 (STAT3), caspase 9, Bax, intracellular reactive oxygen species production, and inflammatory factor and inducible MnSOD expression. Fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) can reveal the differentially expressed proteins of H9C2 cells treated with H2O2 or quercetin. Although 17 identified proteins were altered in H2O2-induced cells, these proteins such as alpha-soluble NSF attachment protein ( α -SNAP), Ena/VASP-like protein (Evl), and isopentenyl-diphosphate delta-isomerase 1 (Idi-1) were reverted by pretreatment with quercetin, which correlates with kinase activation, DNA repair, lipid, and protein metabolism. Quercetin dephosphorylates Src kinase in H2O2-induced H9C2 cells and likely blocks the H2O2-induced inflammatory response through STAT3 kinase modulation. This probably contributes to prevent ischemia/reperfusion injury in cardiomyocytes.
| S-EPMC3612448 | biostudies-literature
Project description:Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation.The acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action.In the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide.In rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide.(ELIXA, ClinicalTrials.gov Identifier: NCT01147250).
| S-EPMC3637243 | biostudies-literature
Project description:We previously developed IM-54 as a novel type of inhibitor of hydrogen-peroxide-induced necrotic cell death. Here, we examined its cell death inhibition profile. IM-54 was found to selectively inhibit oxidative stress-induced necrosis, but it did not inhibit apoptosis induced by various anticancer drugs or Fas ligand, or necroptosis. IM-17, an IM derivative having improved water-solubility and metabolic stability, was developed and confirmed to retain necrosis-inhibitory activity. IM-17 showed cardioprotective effects in an isolated rat heart model and an in vivo arrhythmia model, suggesting that IM derivatives may have therapeutic potential.
| S-EPMC5846036 | biostudies-literature
Project description:Following acute myocardial infarction (MI), early and successful reperfusion is the most effective strategy for reducing infarct size and improving the clinical outcome. However, immediate restoration of blood flow to the ischemic zone results in myocardial damage, defined as "reperfusion-injury". Whereas we previously reported that TVP1022 (the S-isomer of rasagiline, FDA-approved anti-Parkinson drug) decreased infarct size 24 h post ischemia reperfusion (I/R) in rats, in this study we investigated the chronic cardioprotective efficacy of TVP1022 14 days post-I/R. To simulate the clinical settings of acute MI followed by reperfusion therapy, we employed a rat model of left anterior descending artery occlusion for 30 min followed by reperfusion and a follow-up for 14 days. TVP1022 was initially administered postocclusion-prereperfusion, followed by chronic daily administrations. Cardiac performance and remodeling were evaluated using customary and advanced echocardiographic methods, hemodynamic measurements by Millar Mikro-Tip® catheter, and histopathological techniques. TVP1022 administration markedly decreased the remodeling process as illustrated by attenuation of left ventricular enlargement and cardiac hypertrophy (both at the whole heart and the cellular level). Furthermore, TVP1022 inhibited cardiac fibrosis and reduced ventricular BNP levels. Functionally, TVP1022 treatment preserved cardiac wall motion. Specifically, the echocardiographic and most of the direct hemodynamic measures were pronouncedly improved by TVP1022. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R model.
| S-EPMC5226283 | biostudies-literature
Project description:Renal ischemia/reperfusion (I/R) can induce acute kidney injury. Empagliflozin is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. Despite the established cardioprotective functions of empagliflozin, its protective role in renal I/R is unclear. Here, the present study evaluated the renoprotective effects of empagliflozin in a mouse model of renal I/R injury. Male C57/BL6 mice were allocated to sham-operated, I/R, and empagliflozin groups. Kidney pedicles on both sides were clamped for 45 min and were reperfused for 24 h. Empagliflozin (1 mg/kg) was administered to the mice for 2 days preischemia. The GSK-3β inhibitor SB216763 was administered intravenously at the beginning of reperfusion (0.1 mg/kg). Renal function and histological scores were evaluated. The kidneys were taken for immunohistochemical analysis, western blotting and apoptosis measurements. We found that empagliflozin decreased serum levels of creatinine and urea, reduced the average kidney weight-to-tibia length ratio, attenuated tubular damage, reduced renal proinflammatory cytokine expression and inhibited apoptosis in injured kidneys. Furthermore, empagliflozin increased renal glycogen synthase kinase 3β (GSK-3β) phosphorylation post I/R. Pharmacological inhibition of GSK-3β activity mimicked the renal protective effects offered by empagliflozin. In summary, these results support a protective role of empagliflozin against renal I/R injury.
| S-EPMC9652474 | biostudies-literature
Project description:IntroductionAerobic capacity is a strong predictor of cardiovascular mortality. Whether aerobic capacity influences myocardial ischemia and reperfusion (IR) injury is unknown.PurposeTo investigate the impact of intrinsic differences in aerobic capacity and the cardioprotective potential on IR injury.MethodsWe studied hearts from rats developed by selective breeding for high (HCR) or low (LCR) capacity for treadmill running. The rats were randomized to: (1) control, (2) local ischemic preconditioning (IPC) or (3) remote ischemic preconditioning (RIC) followed by 30 minutes of ischemia and 120 minutes of reperfusion in an isolated perfused heart model. The primary endpoint was infarct size. Secondary endpoints included uptake of labelled glucose, content of selected mitochondrial proteins in skeletal and cardiac muscle, and activation of AMP-activated kinase (AMPK).ResultsAt baseline, running distance was 203±7 m in LCR vs 1905±51 m in HCR rats (p<0.01). Infarct size was significantly lower in LCR than in HCR controls (49±5% vs 68±5%, p = 0.04). IPC reduced infarct size by 47% in LCR (p<0.01) and by 31% in HCR rats (p = 0.01). RIC did not modulate infarct size (LCR: 52±5, p>0.99; HCR: 69±6%, p>0.99, respectively). Phosphorylaion of AMPK did not differ between LCR and HCR controls. IPC did not modulate cardiac phosphorylation of AMPK. Glucose uptake during reperfusion was similar in LCR and HCR rats. IPC increased glucose uptake during reperfusion in LCR animals (p = 0.02). Mitochondrial protein content in skeletal muscle was lower in LCR than in HCR (0.77±0.10 arbitrary units (AU) vs 1.09±0.07 AU, p = 0.02), but not in cardiac muscle.ConclusionAerobic capacity is associated with altered myocardial sensitivity to IR injury, but the cardioprotective effect of IPC is not. Glucose uptake, AMPK activation immediately prior to ischemia and basal mitochondrial protein content in the heart seem to be of minor importance as underlying mechanisms for the cardioprotective effects.
| S-EPMC7591019 | biostudies-literature
Project description:Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.
| S-EPMC7665199 | biostudies-literature
Project description:Sonic hedgehog (SHH) signaling pathway is involved in embryonic tissue patterning and development. Our previous work identified, in small rodent model of ischemia reperfusion, SHH as a specific efficient tool to reduce infarct size and subsequent arrhythmias by preventing ventricular repolarization abnormalities. The goal of the present study was to provide a proof of concept of the cardioprotective effect of SHH ligand in a porcine model of acute ischemia. Methods: The antiarrhythmic effect of SHH, either by a recombinant peptide (N-SHH) or shed membrane microparticles harboring SHH ligand (MPsSHH+), was evaluated in a first set of pigs following a short (25 min) coronary artery occlusion (CAO) followed by 24 hours-reperfusion (CAR) (Protocol A). The infarct-limiting effect was evaluated on a second set of pigs with 40 min of coronary artery occlusion followed by 24 hours reperfusion (Protocol B). Electrocardiogram (ECG) was recorded and arrhythmia's scores were evaluated. Area at risk and myocardial infarct size were quantified. Results: In protocol A, administration of N-SHH 15 min. after the onset of coronary occlusion significantly reduced the occurrence of ventricular fibrillation compared to control group. Evaluation of arrhythmic score showed that N-SHH treatment significantly reduced the overall occurrence of arrhythmias. In protocol B, massive infarction was observed in control animals. Either N-SHH or MPsSHH+ treatment reduced significantly the infarct size with a concomitant increase of salvaged area. The reduction in infarct size was both accompanied by a significant decrease in systemic biomarkers of myocardial injury, i.e., cardiac troponin I and fatty acid-binding protein and an increase of eNOS activation. Conclusions: We show for the first time in a large mammalian model that the activation of the SHH pathway by N-SHH or MPsSHH+ offers a potent protection of the heart to ischemia-reperfusion by preventing the reperfusion arrhythmias, reducing the infarct area and the circulating levels of biomarkers for myocardial injury. These data open up potentially theranostic prospects for patients suffering from myocardial infarction to prevent the occurrence of arrhythmias and reduce myocardial tissue damage.
| S-EPMC7086352 | biostudies-literature
Project description:This study aimed to estimate the effects of increasing doses of Allium ursinum methanol extract on cardiac ischemia/reperfusion injury (I/R) with a special emphasis on the role of oxidative stress. Fifty rats were randomly divided into five groups (10 animals per group) depending on the applied treatment as follows: sham, rats who drank only tap water for 28 days and hearts were retrogradely perfused for 80 min without I/R injury, I/R, rats who drank only tap water for 28 days and hearts were exposed to ex vivo I/R injury and rats who consumed increasing doses of A. ursinum 125, 250, and 500 mg/kg for 28 days before I/R injury. Hearts from all rats were isolated and retrogradely perfused according to the Langendorff technique. Parameters of oxidative stress were spectrophotometrically measured in blood, coronary venous effluent, and heart tissue samples. Intake of wild garlic extract for 28 days significantly contributed to the recovery of cardiac function, which was reflected through preserved cardiac contractility, systolic function, and coronary vasodilatory response after ischemia. Also, wild garlic extract showed the potential to modulate the systemic redox balance and stood out as a powerful antioxidant. The highest dose led to the most efficient decrease in cardiac oxidative stress and improve recovery of myocardial function after I/R injury. We might conclude that wild garlic possesses a significant role in cardioprotection and strong antioxidant activity, which implicates the possibility of its use alone in the prevention or as adjuvant antioxidant therapy in cardiovascular diseases (CVD).
| S-EPMC8361798 | biostudies-literature