scholarly journals Propofol Protects against Ischemia/Reperfusion Injury Associated with Reduced Apoptosis in Rat Liver

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ali F. Abdel-Wahab ◽  
Wahid M. Al-Harizy
Keyword(s):  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Group I ◽  
Cellular Apoptosis ◽  
Bax Gene ◽  
Hepatic Protection ◽  
Different Doses

Propofol is an intravenous anesthetic, reported to have a protective effect against ischemia/reperfusion (I/R) injury in heart and brain, but no definite data are available concerning its effect in hepatic I/R. This work investigated the effect of propofol anesthesia on hepatic I/R injury using in vivo rat model. Four groups of rats were included: sham operated, I/R (30 min ischemia and 2 h reperfusion), I/R treated with propofol (10 mg/kg/h), and I/R treated with propofol (20 mg/kg/h). Liver enzyme leakage, TNF-α and caspase-3 levels, and antiapoptotic Bcl-xL/apoptotic Bax gene expression, together with histopathological changes, were used to evaluate the extent of hepatic I/R injury. Compared with sham-operated group, I/R group showed significant increase in serum levels of liver enzymes (ALT, AST), TNF-α, and caspase-3 and significant decrease in the Bcl-xL/Bax ratio, associated with histopathologic damage in liver. Propofol infusion significantly attenuated these changes with reduced hepatic histopathologic lesions compared with nonpreconditioned I/R group. However, no significant differences were found between two groups treated with different doses of propofol. In conclusion, propofol infusion reduced hepatic I/R injury with decreased markers of cellular apoptosis. Therefore, propofol anesthesia may provide a useful hepatic protection during liver surgery.

Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo

2007 ◽  
Vol 293 (1) ◽  
pp. L162-L169 ◽  
Author(s):  
Kai Nowak ◽  
Sandra Weih ◽  
Roman Metzger ◽  
Ronald F. Albrecht ◽  
Stefan Post ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Dry Weight ◽  
Serum Levels ◽  
Converting Enzyme ◽  
Pulmonary Endothelium ◽  
Preferential Expression

Limitation of reactive oxygen species-mediated ischemia-reperfusion (I/R) injury of the lung by vascular immunotargeting of antioxidative enzymes has the potential to become a promising modality for extension of the viability of banked transplantation tissue. The preferential expression of angiotensin-converting enzyme (ACE) in pulmonary capillaries makes it an ideal target for therapy directed toward the pulmonary endothelium. Conjugates of ACE monoclonal antibody (MAb) 9B9 with catalase (9B9-CAT) have been evaluated in vivo for limitation of lung I/R injury in rats. Ischemia of the right lung was induced for 60 min followed by 120 min of reperfusion. Sham-operated animals (sham, n = 6) were compared with ischemia-reperfused untreated animals (I/R, n = 6), I/R animals treated with biotinylated catalase (CAT, n = 6), and I/R rats treated with the conjugates (9B9-CAT, n = 6). The 9B9-CAT accumulation in the pulmonary endothelium of injured lungs was elucidated immunohistochemically. Arterial oxygenation during reperfusion was significantly higher in 9B9-CAT (221 ± 36 mmHg) and sham (215 ± 16 mmHg; P < 0.001 for both) compared with I/R (110 ± 10 mmHg) and CAT (114 ± 30 mmHg). Wet-dry weight ratio of I/R (6.78 ± 0.94%) and CAT (6.54 ± 0.87%) was significantly higher than of sham (4.85 ± 0.29%; P < 0.05), which did not differ from 9B9-CAT (5.58 ± 0.80%). The significantly lower degree of lung injury in 9B9-CAT-treated animals compared with I/R rats was also shown by decreased serum levels of endothelin-1 (sham, 18 ± 9 fmol/mg; I/R, 42 ± 12 fmol/mg; CAT, 36 ± 11 fmol/mg; 9B9-CAT, 26 ± 9 fmol/mg; P < 0.01) and mRNA for inducible nitric oxide synthase (iNOS) [iNOS-GAPDH ratio: sham, 0.15 ± 0.06 arbitrary units (a.u.); I/R, 0.33 ± 0.08 a.u.; CAT, 0.26 ± 0.05 a.u.; 9B9-CAT, 0.14 ± 0.04 a.u.; P < 0.001]. These results validate immunotargeting by anti-ACE conjugates as a prospective and specific strategy to augment antioxidative defenses of the pulmonary endothelium in vivo.

Abstract P280: Deletion of Cardiac Ankyrin Repeat Kinase Reduces Ischemia/Reperfusion Injury in the Heart in Vivo

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Ronald J Vagnozzi ◽  
Gregory Gatto ◽  
Lara Kallander ◽  
Victoria Ballard ◽  
Brian Lawhorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Ankyrin Repeat ◽  
Ischemic Heart ◽  
Acute Injury ◽  
Wild Type

Ischemic heart disease impacts millions of Americans and can progress to heart failure. Current therapies do not address this progression and new therapeutic targets are needed. One novel potential target is cardiac ankyrin repeat kinase (CARK, also troponin I interacting kinase; TNNI3K). CARK is expressed only in the heart and is significantly up-regulated in failing human hearts. Beyond this, little is known about CARK’s biological roles. To determine CARK’s function in the injured heart we subjected transgenic (Tg) mice expressing wild-type or kinase-inactive (KI) CARK to 30 minutes of LV ischemia followed by 24 hours of reperfusion (I/R). CARK-Tg mice had significantly larger infarcts (32.2% AAR vs 16.1% in WT littermates, p<0.05) following I/R. Cardiac troponin I (cTnI) serum levels were also significantly elevated in CARK-Tg mice after 24h, consistent with increased injury. Conversely, infarct size was decreased in mice expressing KI CARK and levels of cTnI were reduced, suggesting that blocking CARK activity may protect against acute injury. To test this, we employed an inducible, cardiac-specific knockout mouse (CARK-KO). CARK-KO mice showed a significant reduction in infarct size (20.52% vs 32.9%, p=0.01) as well as cTnI levels post-I/R. To confirm these findings, wild-type mice were treated with a small molecule CARK inhibitor and then were subjected to I/R. CARK inhibition significantly reduced infarct size (10.92% vs 21.74% p<0.01) as well as serum levels of cTnI. These data indicate that loss of CARK reduces myocyte injury and death after I/R. To examine the mechanism of this effect, primary NRVM were either transduced with a CARK adenovirus or treated with one of two selective CARK inhibitors, and then subjected to oxidative stress using H2O2. CARK over-expression worsened, while CARK inhibition significantly blunted H2O2 - induced apoptosis. Taken together, these data suggest that CARK plays an adverse role in the heart’s response to ischemia, in part by increasing apoptosis. Furthermore, inhibition of CARK may protect the ischemic heart by limiting initial cell loss and thus reducing infarct size. These findings enhance understanding of CARK’s role in the heart and provide evidence for CARK as a novel therapeutic target for ischemic injury.

Analyzing the anti-ischemia–reperfusion injury effects of ginsenoside Rb1 mediated through the inhibition of p38α MAPK

2016 ◽  
Vol 94 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Gonghao Li ◽  
Wenhao Qian ◽  
Changyun Zhao
Keyword(s):  
P38 Mapk ◽  
Caspase 3 ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitogen Activated Protein Kinase ◽  
Ginsenoside Rb1 ◽  
Group I ◽  
Tnf Α ◽  
P38α Mapk

Recent studies have demonstrated that ginsenoside Rb1 protects the myocardium from ischemia–reperfusion (I/R) injury. However, the precise mechanisms for this protection have not been determined. This study aimed to determine whether the attenuation of I/R-induced myocardial injury by ginsenoside Rb1 (GS Rb1) is due to inhibition of p38α mitogen-activated protein kinase (MAPK). Sprague–Dawley rats were distributed among 6 treatment groups: sham group; I/R group; p38 MAPK inhibitor SB203580 group (SB + I/R); GS Rb1 group (GS + I/R); p38 MAPK agonist anisomycin group (Ani + I/R); and the GS Rb1 + Ani group (GS + Ani + I/R). All of the anaesthetized rats, except those in the sham group, underwent an open-chest procedure that involved 30 min of myocardial ischemia followed by 2 h of reperfusion. Myocardial infarction size (MIS), caspase-3 activity, and levels of the cytokine tumor necrosis factor alpha (TNF-α) in the myocardium were monitored. The expressions of p38α MAPK, caspase-3, and TNF-α in the myocardium were assayed. GS Rb1 reduced MIS and attenuated caspase-3 activity and the levels of TNF-α in the myocardium. Protein expression of total p38α MAPK was not significantly altered. In the Ani + I/R and I/R groups, the levels of phospho-p38α MAPK were significantly increased compared with the sham group, and these increased levels were reduced with GS Rb1. Hemodynamic parameters were not significantly different between the GS + I/R and SB + I/R groups. GS Rb1 exerts an anti-apoptotic effect that protects against I/R injury by inhibiting p38α MAPK phosphorylation, suggesting that GS Rb1-mediated protection requires the inhibition of p38α MAPK.

scholarly journals Glutathione ameliorates liver markers, oxidative stress and inflammatory indices in rats with renal ischemia reperfusion injury

2018 ◽  
Vol 8 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Hassan Ahmadvand ◽  
Esmaeel Babaeenezhad ◽  
Maryam Nasri ◽  
Leila Jafaripour ◽  
Reza Mohammadrezaei Khorramabadi
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Renal Ischemia ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Control Group ◽  
Group I ◽  
Liver Markers

Introduction: Glutathione (GSH) protects the tissue and cell from oxidative injury. Objectives: In the current study, we investigated the possible effects of GSH on liver markers, oxidative stress and inflammatory indices in rat with renal ischemia reperfusion (RIR) injury. Materials and Methods: Twenty-four adult male Wistar rats were divided into 3 groups (n=8). Group I (the control group), group II (the RIR group) received saline (0.25 mL/d, intraperitoneally; i.p.), group III as the RIR group that received GSH (100 mg/kg/d, i.p.). The treatment with saline or GSH began daily 14 days before RIR induction. RIR was induced by clamping renal pedicles for 45 minutes and 24 hours of reperfusion. Results: RIR significantly increased the serum level of nitric oxide (NO), the serum activities of aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), the serum and renal levels of malondialdehyde (MDA), and the serum activity of myeloperoxidase (MPO). However, RIR significantly decreased the serum and renal levels of GSH, serum paraoxonase 1 (PON1) activity, and the serum and renal activities of catalase (CAT) and glutathione peroxidase (GPX). GSH administration could significantly improve the serum activities of AST, GGT, MPO, GPX and PON1 and serum levels of NO, renal MDA, GSH levels, and serum and also renal CAT activities. Conclusion: Our study indicated that GSH administration ameliorated RIR injury in rats by improving the activities of liver markers and antioxidant enzymes, the levels of MDA, NO, GSH and MPO activity.

Abstract 1483: The Absence of PI3K γ is Beneficial in a Mouse Model of Myocardial Ischemia/Reperfusion

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Bernhard J Haubner ◽  
Julia Schwaighofer ◽  
Florian Huber ◽  
Greg Neely ◽  
Keiji Kuba ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Troponin T ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Myocardial Ischemia Reperfusion

Introduction - Phosphoinositide 3-Kinase gamma (PI3Kγ) is a well-known key enzyme in inflammation pathways. Emerging data demonstrate that PI3Kγ plays a distinct role in cardiomyocytes, but its influence in the setting of myocardial ischemia and reperfusion is still an enigma. To clarify these effects we examined the morphology and contractility of PI3Kγ−/−hearts after ischemia and reperfusion. Methods - PI3Kγ knock out (KO) mice and C57 Bl6 wild type (WT) mice were subjected to 30 minutes of ischemia followed by 3 hours, 1 week and 3 weeks of reperfusion. We therefore reversibly ligated the left anterior descending artery (LAD) in an in vivo model and harvested the myocardium after the defined time of reperfusion. Histological sections were stained with H&E and Masson Trichrome in order to measure the area of infartion and the amount of interstitial fibrosis. Furthermore, Troponin T serum levels were determined and transthoracic echocardiography was performed for measuring the differences in myocardial contractiliy. Results - Comparing PI3Kγ KO mice with WT mice, we found a significant decrement of Troponin T serum levels in the transgenic group 3 hours after reperfusion (0.77±0.28 vs. 1.28±0.48 ng/ml, p<0.001). In addition, a distinct reduction of myocardial infarction was observed in the KO group compared to the WT mice (3 hours: 1.18±0.31 vs. 1.78±0.45 mm 2 , p=0.001; 1 week: 0.88±0.32 vs. 1.29±0.34 mm 2 , p=0.001; 3 weeks: 0.62±0.18 vs. 1.87±0.59 mm 2 , p<0.001). Furthermore, we showed a matching smaller quantity of myocardial fibrosis in the transgenic cohort (1 week: score 1.23±0.6 vs. 2.13±0.74, p=0.005; 3 weeks: score 1.08±0.79 vs. 2±0.71, p=0.014). Fractional shortening (FS) analysis determined by echocardiography revealed significantly enhanced myocardial contractility in PI3Kγ lacking mice after ischemia and reperfusion (1 week: 37.85±7.71 vs. 23.75±8.78 %FS, p=0.007; 3 weeks: 30.67±4.87 vs. 23.7±7.47 %FS, p=0.043). Conclusions - Our data provide the first evidence for the crucial role of PI3Kγ signalling in myocardial ischemia/reperfusion injury: PI3Kγ deficient mice show a significantly better outcome concerning infarction area, Troponin T elevation, scar size, fibrosis, and contractility at all stages of reperfusion (3 hours to 3 weeks).

The intermediary metabolite pyruvate attenuates stunning and reduces infarct size in in vivo porcine myocardium

2004 ◽  
Vol 286 (2) ◽  
pp. H517-H524 ◽  
Author(s):  
Gentian Kristo ◽  
Yukihiro Yoshimura ◽  
Jianli Niu ◽  
Byron J. Keith ◽  
Robert M. Mentzer ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Group I ◽  
Intermediary Metabolite ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

The intermediary metabolite pyruvate has been shown to exert significant beneficial effects in in vitro models of myocardial oxidative stress and ischemia-reperfusion injury. However, there have been few reports of the ability of pyruvate to attenuate myocardial stunning or reduce infarct size in vivo. This study tested whether supraphysiological levels of pyruvate protect against reversible and irreversible in vivo myocardial ischemia-reperfusion injury. Anesthetized, open-chest pigs ( n = 7/group) underwent 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion to induce stunning. Load-insensitive contractility measurements of regional preload recruitable stroke work (PRSW) and PRSW area (PRSWA) were generated. Vehicle or pyruvate (100 mg/kg iv bolus + 10 mg·kg–1·min–1 intra-atrial infusion) was administered during ischemia and for the first hour of reperfusion. In infarct studies, pigs ( n = 6/group) underwent 1 h of LAD ischemia and 3 h of reperfusion. Group I pigs received vehicle or pyruvate for 30 min before and throughout ischemia. In group II, the infusion was extended through 1 h of reperfusion. In the stunning protocol, pyruvate significantly improved the recovery of PRSWA at 1 h (50 ± 4% vs. 23 ± 3% in controls) and 3 h (69 ± 5% vs. 39 ± 3% in controls) reperfusion. Control pigs exhibited infarct sizes of 66 ± 1% of the area at risk. The pyruvate I protocol was associated with an infarct size of 49 ± 3% ( P < 0.05), whereas the pyruvate II protocol was associated with an infarct size of 30 ± 2% ( P < 0.05 vs. control and pyruvate I). These findings suggest that pyruvate attenuates stunning and decreases myocardial infarction in vivo in part by reduction of reperfusion injury. Metabolic interventions such as pyruvate should be considered when designing the optimal therapeutic strategies for limiting myocardial ischemia-reperfusion injury.

scholarly journals Study of immediate changes in blood coagulation in an experimental model of ischemia/reperfusion injury of the kidney

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
N M B Gamil ◽  
A M Abdelrahman ◽  
D A A Darwish ◽  
E Ahmed
Keyword(s):  
Reperfusion Injury ◽  
Blood Coagulation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Renal Ischemia ◽  
Thrombin Time ◽  
Coagulation Parameters ◽  
Ischemic Reperfusion ◽  
Group I

Abstract Introduction Ischemia- reperfusion injury (IRI) in the kidney triggers multifaceted network of plasma cascades including the complement, coagulation, kinins, and fibrinolytic system, which play major role in the reperfusion-triggered inflammatory process. Aim of the work The aim of the present study was to investigate changes in blood coagulation parameters immediately after ischemia and after ischemia/reperfusion of the kidney in adult rats of both sexes. Materials and Methods The study was carried out on 56 adult albino rats of both sexes weighing 160-220 gm. Rats were randomly allocated into 5 experimental groups as follows: Control rat group (C; n = 10). Sham1- operated rat group (SH1; n = 10) subjected to all the procedures of the I rat group except for renal ischemia and were sacrificed after 45 minutes. Ischemic rat group (I; n = 10) subjected to renal ischemia for 45 min, then were sacrificed. Sham 2 operated rat group 2 (SH2; n = 10) subjected to all the procedures of IR – rat group except for renal ischemia and reperfusion and were sacrificed after 1½ hour. Ischemic/reperfusion rat group (IR; n = 10) subjected to renal ischemia for 45 min, then reperfusion for 45 minutes, then were immediately sacrificed. All rats were subjected to estimation of body weight (BW), absolute and relative kidney weights (AKW and RKW), hemoglobin (Hb) and hematocrit (Ht.) values, clotting time, prothrombin time (PT), activated partial thromboplastin time (PTT), thrombin time (TT) and serum levels of urea (Ur.) and creatinine (Cr.). Results I rat group showed insignificant changes in AKW and RKW, CT, APTT, PT and TT compared to SH1 and C rat groups. However they showed significant elevation in Hb content, Ht. value and serum levels of Ur. and Cr. compared to C rat group. IR rat group showed significant increase in AKW and RKW compared to SH2, I and C rat groups. Also they showed significant increase in Hb. content, Ht. value and serum levels of Ur. and Cr. compared to C rat group. However they showed no significant change in their CT, APTT, PT and TT compared to SH2, I and C rat groups Conclusion Coagulation parameters are not changed immediately after kidney ischemic/reperfusion and may not contribute to the immediate pathophysiological changes of ischemic reperfusion injury.

Effects of Morphine Postconditioning on Myocardial Ischemia-Reperfusion Injury in Rats In Vivo

2013 ◽  
Vol 680 ◽  
pp. 617-619 ◽  
Author(s):  
Da Peng Gao ◽  
Guo Qing Zhao ◽  
Jia Wang ◽  
Ming Gao
Keyword(s):  
Superoxide Dismutase ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Group I ◽  
Cardiac Apoptosis ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objective.To investigate the effects of morphine postconditioning on Myocardial ischemia reperfusion injury in rats in vivo. Methods. To randomly divide 40 male SD rats equally into 4 groups, including Sham group in which the chest was opened without ligating the left coronary artery, ischemia-reperfusion group(Group I/R ), ischemic preconditioning group(Group IPC ) and morphine postconditioning group(GroupMOR) in which 0. 3 mg/kg morphine was given intravenously 5 min before reperfusion. The left anterior descending coronary arterys(LAD) of rats in five groups are ligated for 30 minutes and are re-perfused for 90 minutes. Cardiac Apoptosis was determined quantitatively by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL） methods． To calculate the concentration of the serum malondialdehyde(MDA) with Thiobarbituric acid (TBA) reaction method and the activity of the superoxide dismutase (SOD) with xanthine oxidase reaction method. Result. Comparing with Group S, the quantity of the cardiac apoptosis in Group I/R, IPC and MOR rised in different levels. Comparing with Group 1/R, the quantity of the cardiac apoptosis in Group IPC and MOR reduced obviously. Comparing with Group 1/R, the concentration of the serum malondialdehyde (MDA) in the other four groups all reduced and the activity of the superoxide dismutase increased. Conclusion. Morphine postconditioning can significantly reduce myocardial apoptosis induced by ischemia-reperfusion injury，reduce myocardial infarct size, decrease the concentration of MDA, and increase the activity of SOD. Therefore, morphine postconditioning has protective effects on myocardial ischemia-reperfusion injury in rats in vivo. Morphine is a potent kind of opioid analgesics, which is widely used in clinical anesthesia. However, further studies are needed on effects of morphine postconditioning on myocardial ischemia reperfusion injury. In order to provide the foundations for clinical application, the authors investigate the effects of morphine postconditioning on myocardial ischemia reperfusion injury through comparison and analysis of the cardiac apoptosis, the concentration of the serum malondialdehyde (MDA) and the activity of the superoxide dismutase (SOD) in Group S, I/R, IPC and MOR.

scholarly journals Sodium-Glucose Co-transporter-2 Inhibitor of Dapagliflozin Attenuates Myocardial Ischemia/Reperfusion Injury by Limiting NLRP3 Inflammasome Activation and Modulating Autophagy

2022 ◽  
Vol 8 ◽  
Author(s):  
Yong-Wei Yu ◽  
Jia-Qun Que ◽  
Shuai Liu ◽  
Kai-Yu Huang ◽  
Lu Qian ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
High Dose ◽  
Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Background: The sodium-glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin improves cardiovascular outcomes in patients with type 2 diabetes in a manner that is partially independent of its hypoglycemic effect. These observations suggest that it may exert a cardioprotective effect by another mechanism. This study explored the effects of dapagliflozin on myocardial ischemia/reperfusion injury in a mouse model.Materials and Methods: For the in vivo I/R studies, mice received 40 mg/kg/d dapagliflozin, starting 7 days before I/R. Evans Blue/TTC double-staining was used to determine the infarct size. Serum levels of cTnI, CK-MB, and LDH were measured. Inflammation, autophagy protein expression, and caspase-1 activity changes were measured at the protein level. Primary cardiomyocytes were used to investigate the direct effect of dapagliflozin on cardiomyocytes and to verify whether they have the same effect as observed in in vivo experiments.Result: A high dose of dapagliflozin significantly reduced infarct size and decreased the serum levels of cTnI, CK-MB, and LDH. Dapagliflozin also reduced serum levels of IL-1β, reduced expression of myocardial inflammation-related proteins, and inhibited cardiac caspase-1 activity. The treatment restored autophagy flux and promoted the degradation of autophagosomes. Relief of inflammation relied on autophagosome phagocytosis of NLRP3 and autophagosome clearance after lysosome improvement. 10 μM dapagliflozin reduced intracellular Ca2+ and Na+ in primary cardiomyocytes, and increasing NHE1 and NCX expression mitigated dapagliflozin effects on autophagy.Conclusion: Dapagliflozin protects against myocardial ischemia/reperfusion injury independently of its hypoglycemic effect. High-dose dapagliflozin pretreatment might limit NLRP3 inflammasome activation and mediate its selective autophagy. Dapagliflozin directly acts on cardiomyocytes through NHE1/NCX.

scholarly journals β-Sitosterol Protects against Myocardial Ischemia/Reperfusion Injury via Targeting PPARγ/NF-κB Signalling

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Fengxia Lin ◽  
Luhua Xu ◽  
Meizhu Huang ◽  
Bin Deng ◽  
Weiwei Zhang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia/reperfusion (I/R) injury is a clinically severe complication, which can cause high rates of disability and mortality particularly in patients with myocardial infarction, yet the molecular mechanisms underlying this process remain unclear. This study aimed to explore the protective effects of β-sitosterol against myocardial I/R injury and to elucidate the underlying molecular mechanisms. Our results showed that hypoxia/reoxygenation (H/R) treatment suppressed cell viability, induced cell apoptosis and reactive oxygen species production, increased caspase-3 and -9 activities, upregulated caspase-3 and -9 protein expressions, downregulated the Bcl-2 protein expression, and reduced the mitochondrial membrane potential. β-Sitosterol treatment attenuated H/R-induced cardiomyocyte injury. Moreover, β-sitosterol treatment counteracted the inhibitory effects of H/R treatment on the peroxisome proliferator-activated receptor gamma (PPARγ) expression and enhanced effects of H/R treatment on the NF-κB expression in cardiomyocytes. Furthermore, inhibition of PPARγ impaired the protective actions of β-sitosterol against H/R-induced cardiomyocyte injury. In the I/R rats, β-sitosterol treatment reduced the myocardial infarcted size and apoptosis, which was attenuated by the inhibition of PPARγ. In conclusion, our results demonstrate that β-sitosterol protected against in vitro H/R-induced cardiomyocyte injury and in vivo myocardial I/R injury. The β-sitosterol-mediated cardioprotective effects may involve the modulation of PPARγ/NF-κB signalling during myocardial I/R injury. Further studies are required to further explore the clinical application of β-sitosterol in the myocardial I/R injury.

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