scholarly journals Induction of Glutathione Synthesis Provides Cardioprotection Regulating NO, AMPK and PPARa Signaling in Ischemic Rat Hearts

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 631
Author(s):  
Yulia V. Goshovska ◽  
Raisa A. Fedichkina ◽  
Volodymyr V. Balatskyi ◽  
Oksana O. Piven ◽  
Pawel Dobrzyn ◽  
...  
Keyword(s):  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Glucose Consumption ◽  
Complete Recovery ◽  
Antioxidant Defence ◽  
Glutamate Cysteine Ligase ◽  
Glutathione Synthesis ◽  
Rat Hearts ◽  
Hydrogen Sulfide Production

Glutathione (GSH) is essential for antioxidant defence, and its depletion is associated with tissue damage during cardiac ischemia-reperfusion (I/R). GSH is synthesized by the glutamate-cysteine ligase enzyme (GCL) from L-cysteine, which alternatively might be used for hydrogen sulfide production by cystathionine-gamma-lyase (CSE). Here, we have investigated whether in vivo treatment with L-cysteine and an inhibitor of CSE,D,L-propargylglycine (PAG), can modulate cardiac glutathione and whether this treatment can influence heart resistance to I/R in a Langendorff isolated rat hearts model. Pretreatment with PAG + L-cysteine manifested in pronounced cardioprotection, as there was complete recovery of contractile function; preserved constitutive NOS activity; and limited the production of reactive oxygen and nitrogen species in the ischemized myocardium. Cardiac GSH and GSSG levels were increased by 3.5- and 2.1-fold in PAG + L-cysteine hearts and were 3.3- and 3.6-fold higher in PAG + L-cysteine + I/R compared to I/R heart. The cardioprotective effect of PAG + L-cysteine was completely abolished by an inhibitor of GCL, DL-buthionine-(S,R)-sulfoximine. Further analysis indicated diminished fatty acid β-oxidation, increased glucose consumption and anaerobic glycolysis, and promoted OXPHOS proteins and SERCA2 in PAG + L-cysteine + I/R compared to the I/R group. PAG + L-cysteine inhibited PPARα and up-regulated AMPK signalling in the heart. Thus, induction of glutathione synthesis provided cardioprotection regulating NO, AMPK and PPARa signaling in ischemic rat hearts.

Glutathione supplementation and training increases myocardial resistance to ischemia-reperfusion in vivo

2001 ◽  
Vol 281 (2) ◽  
pp. H679-H688 ◽  
Author(s):  
P. R. Ramires ◽  
L. L. Ji
Keyword(s):  
Oxidative Damage ◽  
Antioxidant Defense ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Group Versus ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Lactate Dehydrogenase Release

The present study examined the effects of oral reduced glutathione (GSH) supplementation in conjunction with endurance training on contractile function, antioxidant defense, and oxidative damage in response to ischemia-reperfusion (I/R) in rat hearts. Female Sprague-Dawley rats (age 4 mo, n = 72) were randomly assigned to a treadmill-trained (T; 25 m/min, 15% grade, for 75 min/day, 5 days/wk, for 10 wk) or untrained (U) group. Each group was further divided into rats receiving 5 g GSH/kg diet during the final 17 days of training (GSH-S) and control (C) groups. One-half of each group of rats was subjected to I/R by surgical occlusion of the main coronary artery for 45 min, followed by 30-min reperfusion or sham operation. Left ventriclar (LV) peak systolic pressure (LVSP) and contractility (+dP/d t), measured with a catheter inserted into the LV via the carotid artery, decreased with I/R in all groups ( P< 0.05). However, LVSP with I/R in the T/GSH-S group was 9.5%, 17%, and 18% higher ( P < 0.05) than that in the U/GSH-S, T/C, and U/C groups, respectively. +dP/d t with I/R was 19%, 27%, and 29% ( P < 0.05) greater in the T/GSH-S group versus the T/C, U/GSH-S, and U/C groups, respectively. I/R decreased heart GSH content by 12–17% ( P < 0.05) and increased oxidized glutathione (GSSG) by 20–27% ( P < 0.05). T/GSH-S hearts showed 15% higher GSH ( P < 0.05) and a 32% higher GSH-to-GSSG ratio ( P < 0.05) than the U/C group at the end of I/R. Myocardial superoxide dismutase, GSH peroxidase, glutathione reductase, and γ-glutamyl transpeptidase activities were increased with treadmill training in both GSH-S and C rats. I/R induced myocardial lipid peroxidation and lactate dehydrogenase release were attenuated with T/GSH-S treatment. The present data indicate that training in conjunction with dietary GSH supplementation can increase myocardial GSH content and antioxidant defense capacity, thereby protecting the intact heart against oxidative damage and functional retardation caused by I/R.

Arachidonic acid causes postischemic dysfunction in control but not diabetic hearts

1990 ◽  
Vol 258 (4) ◽  
pp. H923-H930 ◽  
Author(s):  
G. M. Pieper
Keyword(s):  
Arachidonic Acid ◽  
Free Radical ◽  
Contractile Function ◽  
Oxygen Free Radical ◽  
Free Radical Scavengers ◽  
Diabetic Rat ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Rat Hearts

Isovolumically perfused control and chronic diabetic rat hearts were subjected to 20 min of global ischemia plus 30 min of reperfusion at preischemic flow rates. Recoveries of contractile function during reperfusion were similar in both groups. Addition of arachidonic acid produced profound postischemic dysfunction in nondiabetic hearts (isovolumic minute work = 19 +/- 8 vs. 86 +/- 10% of preischemic levels after 30 min), whereas arachidonic acid had no detrimental effect in diabetic hearts. Arachidonic acid also augmented endogenous prostacyclin release in control hearts (untreated 2.28 +/- 0.23 ng/ml; arachidonic acid 4.07 +/- 0.22 ng/ml) but failed to alter postischemic prostacyclin release in diabetic hearts. The arachidonic acid-induced postischemic dysfunction was significantly attenuated by coadministration of the oxygen free radical scavengers, superoxide dismutase plus catalase, but not by indomethacin. Thus arachidonic acid-induced dysfunction in normal hearts appears to be related, in part, to free radical production. The intrinsic capacity of the heart to synthesize prostacyclin as a result of ischemia and reperfusion does not appear to be impaired by diabetes. In contrast, the arachidonic acid-induced increase in prostacyclin following ischemia is blunted in the diabetic heart. Although chronic diabetic hearts showed increased tolerance to arachidonic acid-induced dysfunction during reperfusion, a defect in prostacyclin stimulation may place the diabetic at greater risk of complications of ischemic reperfusion in vivo by reducing the capacity to adequately respond to the aggregatory and vasospastic actions of increased circulating thromboxane consequent to myocardial ischemia and reperfusion.

PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts

2007 ◽  
Vol 293 (5) ◽  
pp. H2845-H2852 ◽  
Author(s):  
Rong Jiang ◽  
Amanda Zatta ◽  
Hajime Kin ◽  
Ningping Wang ◽  
James G. Reeves ◽  
...  
Keyword(s):  
Infarct Size ◽  
Kinase Inhibitor ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Rat Hearts ◽  
Sparing Effect ◽  
Myocardial Ischemia Reperfusion

Protease-activated receptor-2 (PAR-2) may have proinflammatory effects in some tissues and protective effects in other tissues. The role of PAR-2 in in vivo myocardial ischemia-reperfusion has not yet been determined. This study tested the hypothesis that PAR-2 activation with the PAR-2 agonist peptide SLIGRL (PAR-2 AP) reduces myocardial infarct size when given at reperfusion in vivo, and this cardioprotection involves the ERK1/2 pathway. Anesthetized rats were randomly assigned to the following groups with 30 min of regional ischemia and 3 h reperfusion: 1) control with saline; 2) vehicle (DMSO); 3) PAR-2 AP, 1 mg/kg given intravenously 5 min before reperfusion; 4) scrambled peptide (SP), 1 mg/kg; 5) the ERK1/2 inhibitor PD-98059 (PD), 0.3 mg/kg given 10 min before reperfusion; 6) the phosphatidylinositol 3-kinase inhibitor LY-294002 (LY), 0.3 mg/kg given 10 min before reperfusion; 7) PD + PAR-2 AP, 0.3 mg/kg PD given 5 min before PAR-2 AP; 8) LY + PAR-2 AP, 0.3 mg/kg LY given 5 min before PAR-2 AP; 9) chelerythrine (Chel) alone, 5 mg/kg given 10 min before reperfusion; and 10) Chel + PAR-2 AP, Chel was given 5 min before PAR-2 AP (10 min before reperfusion). Activation of ERK1/2, ERK5, Akt, and the downstream targets of ERK1/2 [P90 RSK and bcl-xl/bcl-2-associated death promoter (BAD)] was determined by Western blot analysis in separate experiments. PAR-2 AP significantly reduced infarct size compared with control (36 ± 2% vs. 53 ± 1%, P < 0.05), and SP had no effect on infarct size (53 ± 3%). PAR-2 AP significantly increased phosphorylation of ERK1/2, p90RSK, and BAD but not Akt or ERK5. Accordingly, the infarct-size sparing effect of PAR-2 AP was abolished by PD (PAR-2 AP, 36 ± 2% vs. PD + PAR-2 AP, 50 ± 1%; P < 0.05) and by Chel (Chel + PAR-2 AP, 58 ± 2%) but not by LY (PAR-2 AP, 36 ± 2% vs. LY + PAR-2 AP, 38 ± 3%; P > 0.05). Therefore, PAR-2 activation is cardioprotective in the in vivo rat heart ischemia-reperfusion model, and this protection involves the ERK1/2 pathway and PKC.

scholarly journals Physiological and histological changes in skeletal muscle following in vivo gene transfer by electroporation

2011 ◽  
Vol 301 (5) ◽  
pp. C1239-C1250 ◽  
Author(s):  
Joseph A. Roche ◽  
Diana L. Ford-Speelman ◽  
Lisa W. Ru ◽  
Allison L. Densmore ◽  
Renuka Roche ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Green Fluorescent Protein ◽  
Intramuscular Injection ◽  
Fluorescent Protein ◽  
Contractile Function ◽  
Complete Recovery ◽  
Secondary Damage ◽  
The Individual ◽  
Green Fluorescent

Electroporation (EP) is used to transfect skeletal muscle fibers in vivo, but its effects on the structure and function of skeletal muscle tissue have not yet been documented in detail. We studied the changes in contractile function and histology after EP and the influence of the individual steps involved to determine the mechanism of recovery, the extent of myofiber damage, and the efficiency of expression of a green fluorescent protein (GFP) transgene in the tibialis anterior (TA) muscle of adult male C57Bl/6J mice. Immediately after EP, contractile torque decreased by ∼80% from pre-EP levels. Within 3 h, torque recovered to ∼50% but stayed low until day 3. Functional recovery progressed slowly and was complete at day 28. In muscles that were depleted of satellite cells by X-irradiation, torque remained low after day 3, suggesting that myogenesis is necessary for complete recovery. In unirradiated muscle, myogenic activity after EP was confirmed by an increase in fibers with central nuclei or developmental myosin. Damage after EP was confirmed by the presence of necrotic myofibers infiltrated by CD68+ macrophages, which persisted in electroporated muscle for 42 days. Expression of GFP was detected at day 3 after EP and peaked on day 7, with ∼25% of fibers transfected. The number of fibers expressing green fluorescent protein (GFP), the distribution of GFP+ fibers, and the intensity of fluorescence in GFP+ fibers were highly variable. After intramuscular injection alone, or application of the electroporating current without injection, torque decreased by ∼20% and ∼70%, respectively, but secondary damage at D3 and later was minimal. We conclude that EP of murine TA muscles produces variable and modest levels of transgene expression, causes myofiber damage due to the interaction of intramuscular injection with the permeabilizing current, and that full recovery requires myogenesis.

Ischemic preconditioning of the whole heart confers protection on subsequently isolated ventricular myocytes

2008 ◽  
Vol 294 (1) ◽  
pp. H524-H531 ◽  
Author(s):  
Glenn C. Rodrigo ◽  
Nilesh J. Samani
Keyword(s):  
Ischemic Preconditioning ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Isolated Cells ◽  
Cellular Models ◽  
Whole Heart ◽  
Intact Heart

Current cellular models of ischemic preconditioning (IPC) rely on inducing preconditioning in vitro and may not accurately represent complex pathways triggered by IPC in the intact heart. Here, we show that it is possible to precondition the intact heart and to subsequently isolate individual ventricular myocytes that retain the protection triggered by IPC. Myocytes isolated from Langendorff-perfused hearts preconditioned with three cycles of ischemia-reperfusion were exposed to metabolic inhibition and reenergization. Injury was assessed from induction of hypercontracture and loss of Ca2+ homeostasis and contractile function. IPC induced an immediate window of protection in isolated myocytes, with 64.3 ± 7.6% of IPC myocytes recovering Ca2+ homeostasis compared with 16.9 ± 2.4% of control myocytes ( P < 0.01). Similarly, 64.1 ± 5.9% of IPC myocytes recovered contractile function compared with 15.3 ± 2.2% of control myocytes ( P < 0.01). Protection was prevented by the presence of 0.5 mM 5-hydroxydecanoate during the preconditioning stimulus. This early protection disappeared after 6 h, but a second window of protection developed 24 h after preconditioning, with 54.9 ± 4.7% of preconditioned myocytes recovering Ca2+ homeostasis compared with 12.6 ± 2.9% of control myocytes ( P < 0.01). These data show that “true” IPC of the heart confers both windows of protection in the isolated myocytes, with a similar temporal relationship to in vivo preconditioning of the whole heart. The model should allow future studies in isolated cells of the protective mechanisms induced by true ischemia.

scholarly journals Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion

2011 ◽  
Vol 300 (2) ◽  
pp. H702-H711 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Chun-An Chen ◽  
Lin Xie ◽  
...  
Keyword(s):  
Heart Rate ◽  
Thyroid Hormone ◽  
Myocardial Ischemia ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Metabolism ◽  
Mouse Heart ◽  
Myocardial Ischemia Reperfusion

There is emerging evidence that treatment with thyroid hormone (TH) can improve postischemic cardiac function. 3,5-Diiodothyropropionic acid (DITPA), a TH analog, has been proposed to be a safer therapeutic agent than TH because of its negligible effects on cardiac metabolism and heart rate. However, conflicting results have been reported for the cardiac effects of DITPA. Importantly, recent clinical trials demonstrated no symptomatic benefit in patients with DITPA despite some improved hemodynamic and metabolic parameters. To address these issues, dose-dependent effects of DITPA were investigated in mice for baseline cardiovascular effects and postischemic myocardial function and/or salvage. Mice were treated with subcutaneous DITPA at 0.937, 1.875, 3.75, or 7.5 mg·kg−1·day−1 for 7 days, and the results were compared with untreated mice for ex vivo and/or in vivo myocardial ischemia-reperfusion (I/R). DITPA had no effects on baseline body temperature, body weight, or heart rate; however, it mildly increased blood pressure. In isolated hearts, baseline contractile function was significantly impaired in DITPA-pretreated mice; however, postischemic recovery was comparable between untreated and DITPA-treated groups. In vivo baseline cardiac parameters were significantly affected by DITPA, with increased ventricular dimensions and decreased contractile function. Importantly, DITPA-treated mice demonstrated high prevalence of fatal cardiac rhythm abnormalities during in vivo ischemia and/or reperfusion. There were no improvements in myocardial infarction and postischemic fractional shortening with DITPA. Myocardial sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and heat shock protein (HSP) levels remained unchanged with DITPA treatment. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R.

scholarly journals Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury

2013 ◽  
Vol 304 (2) ◽  
pp. H294-H302 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Mohammad T. Elnakish ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Mazin A. Alhaj ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Active Form ◽  
Mutant Form ◽  
Cardiac Contractile Function ◽  
The Impact

The GTP-binding protein Rac regulates diverse cellular functions including activation of NADPH oxidase, a major source of superoxide production (O2·−). Rac1-mediated NADPH oxidase activation is increased after myocardial infarction (MI) and heart failure both in animals and humans; however, the impact of increased myocardial Rac on impending ischemia-reperfusion (I/R) is unknown. A novel transgenic mouse model with cardiac-specific overexpression of constitutively active mutant form of Zea maize Rac D (ZmRacD) gene has been reported with increased myocardial Rac-GTPase activity and O2·− generation. The goal of the present study was to determine signaling pathways related to increased myocardial ZmRacD and to what extent hearts with increased ZmRacD proteins are susceptible to I/R injury. The effect of myocardial I/R was examined in young adult wild-type (WT) and ZmRacD transgenic (TG) mice. In vitro reversible myocardial I/R for postischemic cardiac function and in vivo regional myocardial I/R for MI were performed. Following 20-min global ischemia and 45-min reperfusion, postischemic cardiac contractile function and heart rate were significantly reduced in TG hearts compared with WT hearts. Importantly, acute regional myocardial I/R (30-min ischemia and 24-h reperfusion) caused significantly larger MI in TG mice compared with WT mice. Western blot analysis of cardiac homogenates revealed that increased myocardial ZmRacD gene expression is associated with concomitant increased levels of NADPH oxidase subunit gp91phox, O2·−, and P21-activated kinase. Thus these findings provide direct evidence that increased levels of active myocardial Rac renders the heart susceptible to increased postischemic contractile dysfunction and MI following acute I/R.

scholarly journals A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics

2021 ◽  
Author(s):  
Huamei He ◽  
Tomas Baka ◽  
James Balschi ◽  
Alykhan S. Motani ◽  
Kathy K. Nguyen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Negative Impact ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Intact Mouse ◽  
Term Survival ◽  
Rat Hearts

Background: Current heart failure (HF) therapies unload the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropes (i.e. calcitropes) stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. A new class of agents - myotropes - activate the sarcomere directly, independent of calcium. We hypothesize that a novel myotrope TA1 increases contractility without the deleterious myocardial energetic impact of a calcitrope dobutamine. Methods: We determined the effect of TA1 in bovine cardiac myofibrils and human cardiac microtissues, ex vivo in mouse cardiac fibers and in vivo in anesthetized normal rats. Effects of increasing concentrations of TA1 or dobutamine on contractile function, phosphocreatine (PCr) and ATP concentrations and ATP production were assessed by 31 P NMR spectroscopy on isolated perfused rat hearts. Results: TA1 increased the rate of myosin ATPase activity in isolated bovine myofibrils and calcium sensitivity in intact mouse papillary fibers. Contractility increased dose dependently in human cardiac microtissues and in vivo in rats as assessed by echocardiography. In isolated rat hearts, TA1 and dobutamine similarly increased rate pressure product (RPP). Dobutamine increased both developed pressure (DevP) and heart rate (HR) accompanied by decreased PCr to ATP ratio and decreased free energy of ATP hydrolysis (ΔG~ ATP ) and elevated left ventricular end-diastolic pressure (LVEDP). In contrast, the TA1 increased DevP without any effect on HR, LVEDP, PCr/ATP ratio or ΔG~ ATP . Conclusions: Novel myotrope, TA1, increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long term survival, myotropes may represent a superior alternative to traditional inotropes in heart failure management.

Sign in / Sign up

Export Citation Format

Share Document