Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

2012 ◽  
Vol 90 (6) ◽  
pp. 811-823 ◽  
Author(s):  
Sri N. Batchu ◽  
Stephen B. Lee ◽  
Victor Samokhvalov ◽  
Ketul R. Chaudhary ◽  
Haitham El-Sikhry ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Left Ventricular ◽  
Ros Generation ◽  
The Novel ◽  
Active Metabolites ◽  
Developed Pressure

Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 µmol·L–1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 µmol·L–1) and sEH–/– mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol·L–1), or the plasma membrane KATP channels (pmKATP) inhibitor (glibenclamide, 10 µmol·L–1) abolished the improved recovery by BI00611953 (1 µmol·L–1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1∝ DNA binding, and delayed the loss of mitochondrial membrane potential (ΔΨm) caused by anoxia–reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

Protection of the reperfused heart by L-propionylcarnitine

1991 ◽  
Vol 71 (4) ◽  
pp. 1518-1522 ◽  
Author(s):  
J. A. Leipala ◽  
R. Bhatnagar ◽  
E. Pineda ◽  
S. Najibi ◽  
K. Massoumi ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Membrane Integrity ◽  
Creatine Phosphate ◽  
Left Ventricular ◽  
Optimal Time ◽  
Dependent Manner ◽  
Cell Membrane Integrity ◽  
Developed Pressure

The effects of L-propionylcarnitine on mechanical function, creatine phosphate and ATP content, and lactate dehydrogenase leakage were studied in isolated perfused rat hearts exposed to global no-flow ischemia for 30 min followed by reperfusion for 20 min. Five and 10 mM L-propionylcarnitine resulted in a 100% recovery of left ventricular-developed pressure, whereas the recovery was only 40% in the hearts perfused without this agent. Ischemia-reperfusion caused a 85% loss of creatine phosphate and a 77% loss of ATP, which was prevented by 10 mM L-propionylcarnitine. Five millimolar L-propionylcarnitine protected the heart from the loss of creatine phosphate but not from the loss of ATP. Ten millimolar L-propionylcarnitine failed to improve the postischemic left ventricular-developed pressure, when it was added to the perfusate only after ischemia. L-propionylcarnitine alleviated the decrease of coronary flow in the reperfused hearts. Lactate dehydrogenase leakage was aggravated in the beginning of the reperfusion period by 10 mM L-propionylcarnitine. This adverse effect was, however, transient. L-Propionylcarnitine provides protection for the postischemic reperfused heart in a dose-dependent manner. The optimal time for administration is before the ischemic insult. High doses of this compound may perturb cell membrane integrity. Moreover, the present data point to an intracellular, metabolic, and perhaps anaplerotic mechanism of action of L-propionylcarnitine in cardiac ischemia-reperfusion injury.

scholarly journals Genetic Deletion or Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Cardiac Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation

2019 ◽  
Vol 20 (14) ◽  
pp. 3502 ◽  
Author(s):  
Ahmed M. Darwesh ◽  
Hedieh Keshavarz-Bahaghighat ◽  
K. Lockhart Jamieson ◽  
John M. Seubert
Keyword(s):  
Nlrp3 Inflammasome ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Inflammasome Activation ◽  
Protective Effects ◽  
Isolated Hearts ◽  
Pyrin Domain ◽  
Cardioprotective Effects

Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response.

Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2018 ◽  
Vol 132 (15) ◽  
pp. 1669-1683 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Lv Function ◽  
Male Wistar Rats ◽  
Group A

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

scholarly journals Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARγ

2016 ◽  
Vol 311 (4) ◽  
pp. R676-R688 ◽  
Author(s):  
Ahmad Hanif ◽  
Matthew L. Edin ◽  
Darryl C. Zeldin ◽  
Christophe Morisseau ◽  
Mohammed A. Nayeem
Keyword(s):  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Hyperemia ◽  
Soluble Epoxide Hydrolase ◽  
Mouse Heart ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH−/− mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline ( P < 0.001) and 5.6-fold higher post-ischemia ( P < 0.001) in sEH−/− compared with sEH+/+ mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold ( P < 0.01) and 3.7-fold ( P < 0.001) higher, respectively in sEH−/− compared with sEH+/+ mice. 13-HODE was also significantly increased at baseline by 71% ( P < 0.01) in sEH−/− vs. sEH+/+ mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains ( P > 0.05), but were decreased postischemia in both groups ( P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+ ( P < 0.001) and 33% in sEH−/− mice ( P < 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+ ( P = 0.04) and sEH−/− mice ( P = 0.04). l-NAME attenuated CRH in both sEH−/− and sEH+/+. These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response.

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

2007 ◽  
Vol 292 (4) ◽  
pp. H1986-H1994 ◽  
Author(s):  
Zhanna Makazan ◽  
Harjot K. Saini ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Left Ventricular ◽  
Cardiac Performance ◽  
Developed Pressure

To study the mechanisms of mitochondrial dysfunction due to ischemia-reperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [ N-acetyl-l-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H2O2) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R.

scholarly journals Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice

PLoS ONE ◽  
2016 ◽  
Vol 11 (1) ◽  
pp. e0145645 ◽  
Author(s):  
Ye Zhu ◽  
Maximilian Blum ◽  
Uwe Hoff ◽  
Tim Wesser ◽  
Mandy Fechner ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury ◽  
Deficient Mice

Acute effects of 17β-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury

2005 ◽  
Vol 288 (1) ◽  
pp. C57-C64 ◽  
Author(s):  
Steven E. Anderson ◽  
Dawn M. Kirkland ◽  
Andrea Beyschau ◽  
Peter M. Cala
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Ovariectomized Rats ◽  
Functional Coupling ◽  
Cytosolic Ph ◽  
Thermodynamic Effect ◽  
17Β Estradiol ◽  
Developed Pressure

Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca2+ accumulation resulting from functional coupling of Na+/Ca2+ exchange (NCE) with stimulated Na+/H+ exchange (NHE1) and 2) 17β-estradiol (E2) stimulates release of NO, which inhibits NHE1. Thus we tested the hypothesis that acute E2 limits myocardial Na+ and therefore Ca2+ accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pHi), Na+ (Na[Formula: see text]), and calcium concentration ([Ca2+]i) in Krebs-Henseleit (KH)-perfused hearts from ovariectomized rats (OVX). Left ventricular developed pressure (LVDP) and lactate dehydrogenase (LDH) release were also measured. Control ischemia-reperfusion was 20 min of baseline perfusion, 40 min of global ischemia, and 40 min of reperfusion. The E2 protocol was identical, except that 1 nM E2 was included in the perfusate before ischemia and during reperfusion. E2 significantly limited the changes in pHi, Na[Formula: see text] and [Ca2+]i during ischemia ( P < 0.05). In control OVX vs. OVX+E2, pHi fell from 6.93 ± 0.03 to 5.98 ± 0.04 vs. 6.96 ± 0.04 to 6.68 ± 0.07; Na[Formula: see text] rose from 25 ± 6 to 109 ± 14 meq/kg dry wt vs. 25 ± 1 to 76 ± 3; [Ca2+]i changed from 365 ± 69 to 1,248 ± 180 nM vs. 293 ± 66 to 202 ± 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 μM Nω-nitro-l-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca2+]i is greater than can be accounted for by the thermodynamic effect of reduced Na[Formula: see text] accumulation on NCE.

scholarly journals Hemidesmus indicusandHibiscus rosa-sinensisAffect Ischemia Reperfusion Injury in Isolated Rat Hearts

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Vinoth Kumar Megraj Khandelwal ◽  
R. Balaraman ◽  
Dezider Pancza ◽  
Táňa Ravingerová
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Moderate Increase ◽  
Dependent Manner ◽  
Hemidesmus Indicus ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Developed Pressure

Hemidesmus indicus(L.) R. Br. (HI) andHibiscus rosa-sinensisL. (HRS) are widely used traditional medicine. We investigated cardioprotective effects of these plants applied for 15 min at concentrations of 90, 180, and 360 μg/mL in Langendorff-perfused rat hearts prior to 25-min global ischemia/120-min reperfusion (I/R). Functional recovery (left ventricular developed pressure—LVDP, and rate of development of pressure), reperfusion arrhythmias, and infarct size (TTC staining) served as the endpoints. A transient increase in LVDP (32%–75%) occurred at all concentrations of HI, while coronary flow (CF) was significantly increased after HI 180 and 360. Only a moderate increase in LVDP (21% and 55%) and a tendency to increase CF was observed at HRS 180 and 360. HI and HRS at 180 and 360 significantly improved postischemic recovery of LVDP. Both the drugs dose-dependently reduced the numbers of ectopic beats and duration of ventricular tachycardia. The size of infarction was significantly decreased by HI 360, while HRS significantly reduced the infarct size at all concentrations in a dose-dependent manner. Thus, it can be concluded that HI might cause vasodilation, positive inotropic effect, and cardioprotection, while HRS might cause these effects at higher concentrations. However, further study is needed to elucidate the exact mechanism of their actions.

Antioxidant tempol suppresses heart cytosolic phospholipase A2α stimulated by chronic intermittent hypoxia

2017 ◽  
Vol 95 (8) ◽  
pp. 920-927 ◽  
Author(s):  
Petra Míčová ◽  
Martina Klevstig ◽  
Kristýna Holzerová ◽  
Marek Vecka ◽  
Jitka Žurmanová ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Chronic Intermittent Hypoxia ◽  
Acute Ischemia ◽  
Left Ventricular Myocardium ◽  
Ros Generation ◽  
Mrna Levels

Adaptation to chronic intermittent hypoxia (CIH) is associated with reactive oxygen species (ROS) generation implicated in the improved cardiac tolerance against acute ischemia–reperfusion injury. Phospholipases A2(PLA2s) play an important role in cardiomyocyte phospholipid metabolism influencing membrane homeostasis. Here we aimed to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2(cPLA2α), its phosphorylated form (p-cPLA2α), calcium-independent (iPLA2), and secretory (sPLA2IIA) at protein and mRNA levels, as well as fatty acids (FA) profile in left ventricular myocardium of adult male Wistar rats. Chronic administration of antioxidant tempol was used to verify the ROS involvement in CIH effect on PLA2s expression and phospholipid FA remodeling. While CIH did not affect PLA2s mRNA levels, it increased the total cPLA2α protein in cytosol and membranes (by 191% and 38%, respectively) and p-cPLA2α (by 23%) in membranes. On the contrary, both iPLA2and sPLA2IIA were downregulated by CIH. CIH further decreased phospholipid n-6 polyunsaturated FA (PUFA) and increased n-3 PUFA proportion. Tempol treatment prevented only CIH-induced cPLA2α up-regulation and its phosphorylation on Ser505. Our results show that CIH diversely affect myocardial PLA2s and suggest that ROS are responsible for the activation of cPLA2α under these conditions.

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