scholarly journals Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation

2007 ◽  
Vol 292 (5) ◽  
pp. H2227-H2236 ◽  
Author(s):  
Norbert Fülöp ◽  
Zhenghao Zhang ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Functional Recovery ◽  
Protein Modification ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Low Flow ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Mitogen Activated Protein ◽  
Hexosamine Biosynthesis ◽  
Nucleocytoplasmic Proteins

We have shown that, in the perfused heart, glucosamine improved functional recovery following ischemia and that this appeared to be mediated via an increase in O-linked N-acetylglucosamine ( O-GlcNAc) levels on nucleocytoplasmic proteins. Several kinase pathways, specifically Akt and the mitogen-activated protein kinases (MAPKs) p38 and ERK1/2, which have been implicated in ischemic cardioprotection, have also been reported to be modified in response to increased O-GlcNAc levels. Therefore, the goals of this study were to determine the effect of ischemia on O-GlcNAc levels and to evaluate whether the cardioprotection resulting from glucosamine treatment could be attributed to changes in ERK1/2, Akt, and p38 phosphorylation. Isolated rat hearts were perfused with or without 5 mM glucosamine and were subjected to 5, 10, or 30 min of low-flow ischemia or 30 min of low-flow ischemia and 60 min of reperfusion. Glucosamine treatment attenuated ischemic contracture and improved functional recovery at the end of reperfusion. Glucosamine treatment increased flux through the hexosamine biosynthesis pathway and increased O-GlcNAc levels but had no effect on ATP levels. Glucosamine did not alter the response of either ERK1/2 or Akt to ischemia-reperfusion; however, it significantly attenuated the ischemia-induced increase in p38 phosphorylation and paradoxically increased p38 phosphorylation at the end of reperfusion. These data support the notion that O-GlcNAc may play an important role as an internal stress response and that glucosamine-induced cardioprotection may be mediated via the p38 MAPK pathway.

scholarly journals Increased O-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis

2007 ◽  
Vol 293 (3) ◽  
pp. H1391-H1399 ◽  
Author(s):  
Jia Liu ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Functional Recovery ◽  
Stress Responses ◽  
Ischemia Reperfusion ◽  
Protein Levels ◽  
Rat Hearts ◽  
Hexosamine Biosynthesis ◽  
Perfused Rat Hearts ◽  
Dependent Protein ◽  
Troponin Release ◽  
Hexosamine Biosynthesis Pathway

We have previously shown that preischemic treatment with glucosamine improved cardiac functional recovery following ischemia-reperfusion, and this was mediated, at least in part, via enhanced flux through the hexosamine biosynthesis pathway and subsequently elevated O-linked N-acetylglucosamine ( O-GlcNAc) protein levels. However, preischemic treatment is typically impractical in a clinical setting; therefore, the goal of this study was to investigate whether increasing protein O-GlcNAc levels only during reperfusion also improved recovery. Isolated perfused rat hearts were subjected to 20 min of global, no-flow ischemia followed by 60 min of reperfusion. Administration of glucosamine (10 mM) or an inhibitor of O-GlcNAcase, O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino- N-phenylcarbamate (PUGNAc; 200 μM), during the first 20 min of reperfusion significantly improved cardiac functional recovery and reduced troponin release during reperfusion compared with untreated control. Both interventions also significantly increased the levels of protein O-GlcNAc and ATP levels. We also found that both glucosamine and PUGNAc attenuated calpain-mediated proteolysis of α-fodrin as well as Ca2+/calmodulin-dependent protein kinase II during reperfusion. Thus two independent strategies for increasing protein O-GlcNAc levels in the heart during reperfusion significantly improved recovery, and this was correlated with attenuation of calcium-mediated proteolysis. These data provide further support for the concept that increasing cardiac O-GlcNAc levels may be a clinically relevant cardioprotective strategy and suggest that this protection could be due, at least in part, to inhibition of calcium-mediated stress responses.

Adenosine antagonism decreases metabolic but not functional recovery from ischemia

1991 ◽  
Vol 260 (1) ◽  
pp. H193-H200 ◽  
Author(s):  
D. A. Angello ◽  
J. P. Headrick ◽  
N. M. Coddington ◽  
R. M. Berne
Keyword(s):  
Functional Recovery ◽  
Left Ventricular ◽  
Low Flow ◽  
Ischemia And Reperfusion ◽  
Constant Flow ◽  
Hemodynamic Parameters ◽  
Isolated Hearts ◽  
Rat Hearts ◽  
Adenosine Antagonism ◽  
Developed Pressure

The effect of adenosine receptor antagonism on function and metabolism was examined in isolated hearts during low flow ischemia and reperfusion. Isovolumic rat hearts perfused at constant flow were subjected to 30 min of ischemia followed by 30 min of reperfusion. Infusion of vehicle or 10 microM 8-phenyltheophylline (8-PT) was initiated 10 min before ischemia and maintained throughout reperfusion. 8-PT infusion had no significant effects on hemodynamic parameters or metabolism preischemia. During ischemia, left ventricular developed pressure declined to approximately 15% of preischemic values in control and 8-PT hearts, and ATP and PCr decreased to approximately 73 and 60% of preischemic values. Inorganic phosphate (Pi) increased to 353 = 41 and 424 +/- 53% of preischemic values in control and 8-PT hearts, respectively. After reperfusion, function recovered to greater than 95% of preischemic levels in control and 8-PT hearts. Unlike control hearts, recovery of metabolites was significantly different during reperfusion in 8-PT hearts (P less than 0.05); ATP, phosphocreatine, and Pi recovered to 82 +/- 8, 71 +/- 8, and 281 +/- 27% of preischemic values, respectively. Venous purine washout was significantly greater (P less than 0.05) during reperfusion in 8-PT hearts (327 +/- 113 nmol) than in control hearts (127 +/- 28 nmol). Blockade of adenosine receptors appears to adversely affect metabolic but not functional recovery in the ischemic-reperfused myocardium.

Dose-dependent protection of cardiac function by propofol during ischemia and early reperfusion in rats: effects on 15-F2t-isoprostane formation

2003 ◽  
Vol 81 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Zhengyuan Xia ◽  
David V Godin ◽  
Thomas K.H Chang ◽  
David M Ansley
Keyword(s):  
Antioxidant Capacity ◽  
Functional Recovery ◽  
Ischemia Reperfusion ◽  
Oxidant Injury ◽  
Control Groups ◽  
Early Reperfusion ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Dose Dependent ◽  
Myocardium Ischemia Reperfusion

We examined the effects of propofol (2,6-diisopropylphenol) on functional recovery and 15-F2t-isoprostane generation during ischemia–reperfusion in Langendorff-perfused rat hearts. Before the induction of 40 min of global ischemia, hearts were perfused (10 min) with propofol at 5 (lo-P) or 12 μg/mL (hi-P) in saline or with saline only (control). During ischemia, saline, lo-P, or hi-P was perfused through the aorta at 60 μL/min. During the first 15 min of reperfusion, propofol (5 or 12 μg/mL) was continued, followed by perfusion with 5 μg/mL propofol for 75 min in both propofol-treated groups. After 90 min of reperfusion (Rep-90), heart tissues were harvested for assessment of antioxidant status. In hi-P, we observed increased latency to and greater reduction of ischemic contracture relative to the lo-P or control groups. 15-F2t-Isoprostane concentrations increased during ischemia and were significantly lower in hi-P and lo-P than in control (P < 0.01). At Rep-90, myocardial functional recovery was greater in both propofol-treated groups relative to control, and it correlated positively with tissue antioxidant capacity preservation. Tissue antioxidant capacity was better preserved in hi-P than in lo-P treatment (P < 0.05). We conclude that oxidant injury occurs during ischemia and reperfusion, and propofol provides dose-dependent protection primarily by enhancing tissue antioxidant capacity and reducing lipid peroxidation.Key words: propofol, myocardium, ischemia–reperfusion, 15-F2t-isoprostane.

scholarly journals Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

2017 ◽  
Vol 41 (3) ◽  
pp. 999-1010 ◽  
Author(s):  
Shasha Zhu ◽  
Tongda Xu ◽  
Yuanyuan Luo ◽  
Yingying Zhang ◽  
Haochen Xuan ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Diastolic Function ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Regulatory Function ◽  
Protective Mechanism ◽  
P38 Mapk Pathway ◽  
Rat Hearts ◽  
R Process

Background/Aims: A major challenge for current therapeutic strategies against ischemia/reperfusion (I/R) is the lack of effective drugs. Considering luteolin enhances the activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) to improve the systolic/diastolic function of rat hearts and cardiomyocytes during the I/R process, we studied the regulatory function of the p38 MAPK pathway in this protective mechanism. Methods: Isolated cardiomyocytes and perfused hearts were separately divided into five groups and used to investigate I/R. The phosphorylation of p38 and phospholamban (p-PLB), the levels and activity of SERCA2a and the levels of proteins related to apoptosis were measured. Apoptotic cells were assessed using the TUNEL assay. Single-cell shortening, Ca2+ transients, and the decay of the mitochondrial membrane potential (Δψm) were detected. Results: The p38 MAPK pathway was activated during the I/R process, and inhibiting it with SB203580 promoted p-PLB, which enhanced the activity of SERCA2a and relieved the calcium overload to promote the recovery of the Δψm and reduce cardiomyocyte apoptosis in I/R. Luteolin also suppressed the activation of the p38 MAPK pathway and showed cardioprotective effects during I/R injury. Conclusions: We conclude that luteolin enhances SERCA2a activity to improve systolic/diastolic function during I/R in rat hearts and cardiomyocytes by attenuating the inhibitive effects of the p38 pathway on p-PLB.

Potential beneficial as well as detrimental effects of chronic treatment with lisinopril and (or) spironolactone on isolated hearts following low-flow ischemia in normal and infarcted rats

2003 ◽  
Vol 81 (9) ◽  
pp. 864-872 ◽  
Author(s):  
Annie Rochetaing ◽  
Catherine Chapon ◽  
Laurent Marescaux ◽  
Anne Le Bouil ◽  
Alain Furber ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Tachycardia ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Ischemia Reperfusion ◽  
Reactive Hyperemia ◽  
Low Flow ◽  
Beneficial Effects ◽  
Rat Hearts ◽  
Contractile Recovery

This study was designed to demonstrate potential beneficial as well as detrimental effects of lisinopril and spironolactone given in combination. In patients with congestive heart failure or myocardial infarction, the use of angiotensin-converting enzyme (ACE) inhibitors may inhibit aldosterone production. Spironolactone, a specific aldo sterone receptor antagonist may exert other independent and additive effects to those of ACE inhibitors. Given the consequences of aldosterone on ischemic hearts, we evaluated the protective effects of spironolactone or lisinopril and combined spironolactone–lisinopril therapy during low-flow ischemia and reperfusion in isolated rat hearts. Normal and infarcted (left coronary artery ligature) male Wistar rats were submitted to chronic action of drugs (0.8 mg·kg–1·day–1 for lisinopril and 8 or 50 mg·kg–1·day–1 for spironolactone) for 1 month. Hearts were rapidly excised and perfused (constant pressure) for a 40-min period of stabilization followed by a 25-min period of global low-flow ischemia and a 30-min reperfusion. In normal rats, spironolactone decreased ischemic and reperfusion contracture, reduced ventricular tachycardia, suppressed action-potential duration dispersion, and increased reactive hyperemia leading to an improvement of contractile recovery. Lisinopril also decreased ventricular tachycardia and action-potential duration dispersion concomitantly with increased reactive hyperemia and better contractile recovery. These beneficial effects of the drugs were lost when the two treatments were combined (lisinopril and 50 mg·kg–1·day–1 spironolactone), despite a synergistic effect on plasmatic K+ and Mg2+. However, an interaction between the ACE inhibitor and spironolactone potentiating the effects of either drug alone was observed with a lower dose of spironolactone (lisinopril and 8 mg·kg–1·day–1 spironolactone). Similar beneficial effects have been noted in infarcted rat hearts on reactive hyperemia, ventricular tachycardia, and contractile recovery with the combined treatment and for both spironolactone concentrations (8 or 50 mg). Chronic spironolactone treatment produces similar beneficial effects to ACE inhibitor treatment on normal rat hearts during an ischemia-reperfusion protocol. Synergistic effects have been observed with the combined therapy when a lower dose of spironolactone was utilized in normal and infarcted rats. However, in the case of a high dose of spironolactone, the two effective drugs seem to cancel each other but only in normal rats.Key words: spironolactone, ACE inhibitors, ischemia–reperfusion, ventricular arrhythmia, action potentials, coronary flow, congestive heart failure.

scholarly journals Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling

2006 ◽  
Vol 25 (2) ◽  
pp. 314-324 ◽  
Author(s):  
Eliana Lucchinetti ◽  
Jianhua Feng ◽  
Rafaela da Silva ◽  
Genrich V. Tolstonog ◽  
Marcus C. Schaub ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Rat Heart ◽  
Cardiac Tissue ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Immunoblot Analysis ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Antisense Odns

Microarray analyses indicate that ischemic and pharmacological preconditioning suppress overexpression of the non-long terminal repeat retrotransposon long interspersed nuclear element 1 (LINE-1, L1) after ischemia-reperfusion in the rat heart. We tested whether L1 overexpression is mechanistically involved in postischemic myocardial damage. Isolated, perfused rat hearts were treated with antisense or scrambled oligonucleotides (ODNs) against L1 for 60 min and exposed to 40 min of ischemia followed by 60 min of reperfusion. Functional recovery and infarct size were measured. Effective nuclear uptake was determined by FITC-labeled ODNs, and downregulation of L1 transcription was confirmed by RT-PCR. Immunoblot analysis was used to assess changes in expression levels of the L1-encoded proteins ORF1p and ORF2p. Immunohistochemistry was performed to localize ORF1/2 proteins in cardiac tissue. Effects of ODNs on prosurvival protein kinase B (Akt/PKB) expression and activity were also determined. Antisense ODNs against L1 prevented L1 burst after ischemia-reperfusion. Inhibition of L1 increased Akt/PKBβ expression, enhanced phosphorylation of PKB at serine 473, and markedly improved postischemic functional recovery and decreased infarct size. Antisense ODN-mediated protection was abolished by LY-294002, confirming the involvement of the Akt/PKB survival pathway. ORF1p and ORF2p were found to be expressed in rat heart. ORF1p showed a predominantly nuclear localization in cardiomyocytes, whereas ORF2p was exclusively present in endothelial cells. ORF1p levels increased in response to ischemia, which was reversed by antisense ODN treatment. No significant changes in ORF2p were noted. Our results demonstrate that L1 suppression favorably affects postischemic outcome in the heart. Modifying transcriptional activity of L1 may represent a novel anti-ischemic therapeutic strategy.

AT1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts

2002 ◽  
Vol 282 (4) ◽  
pp. H1206-H1215 ◽  
Author(s):  
Yi Xu ◽  
Dinender Kumar ◽  
Jason R. B. Dyck ◽  
William R. Ford ◽  
Alexander S. Clanachan ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Enzyme Inhibitor ◽  
Ischemia Reperfusion ◽  
Positive Control ◽  
Receptor Expression ◽  
Acute Ischemia ◽  
Ang Ii ◽  
Rat Hearts

We assessed ANG II type 1 (AT1) and type 2 (AT2) receptor (R) expression and functional recovery after ischemia-reperfusion with or without AT1R/AT2R blockade in isolated working rat hearts. Groups of six hearts were subjected to global ischemia (30 min) followed by reperfusion (30 min) and exposed to no drug and no ischemia-reperfusion (control), ischemia-reperfusion and no drug, and ischemia-reperfusion with losartan (an AT1R antagonist; 1 μmol/l), PD-123319 (an AT2R antagonist; 0.3 μmol/l), N 6-cyclohexyladenosine (CHA, a cardioprotective adenosine A1 receptor agonist; 0.5 μmol/l as positive control), enalaprilat (an ANG-converting enzyme inhibitor; 1 μmol/l), PD-123319 + losartan, ANG II (1 nmol/l), or ANG II + losartan. Compared with controls, ischemia-reperfusion decreased AT2R protein (Western immunoblots) and mRNA (Northern immunoblots, RT-PCR) and impaired functional recovery. PD-123319 increased AT2R protein and mRNA and improved functional recovery. Losartan increased AT1R mRNA (but not AT1R/AT2R protein) and impaired recovery. Other groups (except CHA) did not improve recovery. The results suggest that, in isolated working hearts, AT2R plays a significant role in ischemia-reperfusion and AT2R blockade induces increased AT2R protein and cardioprotection.

scholarly journals Preconditioning limits mitochondrial Ca2+ during ischemia in rat hearts: role of KATP channels

2001 ◽  
Vol 280 (5) ◽  
pp. H2321-H2328 ◽  
Author(s):  
Lianguo Wang ◽  
Gennady Cherednichenko ◽  
Lisa Hernandez ◽  
Jessica Halow ◽  
S. Albert Camacho ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Calcium Concentration ◽  
Myocardial Function ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Mitochondrial Calcium ◽  
Rat Hearts ◽  
Developed Pressure

Prolonged myocardial ischemia results in an increase in intracellular calcium concentration ([Ca2+]i), which is thought to play a critical role in ischemia-reperfusion injury. Ischemic preconditioning (PC) improves myocardial function during ischemia-reperfusion, a process that may involve opening mitochondrial ATP-sensitive potassium (KATP) channels. Because pharmacological limitation of mitochondrial calcium concentration ([Ca2+]m) overload during ischemia-reperfusion has been shown to improve myocardial function, we hypothesized that PC would reduce [Ca2+]m during ischemia-reperfusion and that this effect was mediated by opening mitochondrial KATP channels. Isolated rat hearts were subjected to 25 min of global ischemia and 30 min of reperfusion with or without PC in the presence of mitochondrial KATP channel opening (diazoxide, 100 μM) and blockade [5-hydroxydecanoic acid (5-HD), 100 μM]. Contracture during ischemia (end-diastolic pressure) and functional recovery on reperfusion (developed pressure) were assessed. Total [Ca2+]i and [Ca2+]m were measured using indo 1 fluorescence. Both PC and diazoxide limited the increase in end-diastolic pressure and resulted in greater functional recovery after 30 min of reperfusion, functional effects that were partially or completely abolished by 5-HD. PC and diazoxide also significantly limited the increase in [Ca2+]m during ischemia-reperfusion. In addition, PC lowered [Ca2+]i during reperfusion, whereas diazoxide paradoxically resulted in increased [Ca2+]iduring reperfusion. There was an inverse linear relationship between [Ca2+]m and developed pressure during reperfusion. PC limits the ischemia-induced increase in mitochondrial, but not total, [Ca2+]i, an effect mediated by opening mitochondrial KATP channels. These data suggest that the lowering of mitochondrial calcium overload is a mechanism of cardioprotection in PC.

The stunned myocardium: effect of electrical and mechanical arrest and osmolarity

1988 ◽  
Vol 255 (1) ◽  
pp. H60-H69 ◽  
Author(s):  
W. G. Nayler ◽  
J. S. Elz ◽  
D. J. Buckley
Keyword(s):  
Functional Recovery ◽  
Ischemia Reperfusion ◽  
Complete Recovery ◽  
Inotropic Effect ◽  
Stunned Myocardium ◽  
Equivalent Time ◽  
Rat Hearts ◽  
High K ◽  
Ischemic Episode ◽  
K Concentration

After relatively short periods of ischemia, reperfusion for several hours, or even days, is required to facilitate complete recovery of the ATP stores and mechanical function. The term "stunned" has been applied to these hearts. In the present experiments, isolated, spontaneously beating and electrically paced rat hearts were made ischemic for 10 min and then reperfused with Krebs-Henseleit buffer (KH) for up to 30 min. On reperfusion, functional recovery was impaired and the inotropic effect of Ca2+ blunted. In these experiments, the effect of a period of electrical and/or mechanical quiescence before the ischemic episode was investigated. Electrical quiescence was obtained by raising the KH K+ concentration, whereas mechanical without electrical quiescence was obtained by lowering the KH Ca2+ concentration or adding 2,3-butanedione monoxime (BDM). Mechanical arrest caused by low Ca2+ perfusion before ischemia failed to improve functional recovery on reperfusion. However, introducing a high K+ perfusate or BDM for a few minutes before ischemia significantly improved the recovery during reperfusion. This improvement was neither caused by energy preservation nor an altered "reflow area". The improvement may be caused by the increased osmolarity of KH containing high K+ or BDM, since adding 10 mM sucrose to KH for an equivalent time before ischemia improved recovery and abolished the blunted inotropic effect of Ca2+.

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