Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The purpose of this study was to evaluate the protective effect of a new endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three groups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion. First group of rabbits (n = 6) were treated with 0.35 ml vehicle (40 % propylene glycol, 10 % ethanol in water). The second and third group of rabbits (n = 6-8) were treated with MLA (35 micrograms/kg, i.v.) 12 and 24 hours prior to ischemia and reperfusion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion demonstrated significantly reduced infarct size (12.5 +/- 1.7 and 14.7 +/- 2.1% for 12 and 24 h) when compared with vehicle control (40.4 +/- 8.6%, mean +/- S.E.M, p < 0.05). No significant differences in the infarct size was observed between the 12 and 24 h MLA treated groups. The area at risk was not significantly different between the three groups. Baseline values of heart rate, systolic and diastolic blood pressure were not significantly different between the control and MLA treated groups. However, the systolic as well as diastolic blood pressure during reperfusion were significantly lower in rabbits treated with MLA. Western blot analysis of the protein extracts of the hearts (n = 2/group) demonstrated no increase in the expression of the inducible form of HSP 70 following treatment with MLA. We conclude that MLA has significant anti-infarct effect in rabbit which is not mediated by the cardioprotective protein HSP 70. The anti-infarct effect of this drug is superior to the reported protective effects of delayed ischemic or heat stress preconditioning. We hypothesize that the pharmacologic preconditioning afforded by MLA is accomplished via a unique pathway that bypasses the usual intracellular signaling pathways which lead to the myocardial protection with the expression of heat shock proteins.
Mol Cell Biochem 1996 Mar 09
PMID:Monophosphoryl lipid A induces pharmacologic 'preconditioning' in rabbit hearts without concomitant expression of 70-kDa heat shock protein. 870 70

Recent studies suggest that calcium channel blockers attenuate reversible post-ischemic myocardial dysfunction (myocardial "stunning") in vivo. This beneficial effect, however, has been shown either in open-chest preparations, which are subject to the confounding influence of many unphysiological conditions, or in models in which treatment caused significant hemodynamic alterations. Furthermore, all of the studies have been conducted in the dog, and almost all of them have examined the effect of calcium antagonists after a single ischemic episode. The goal of the present investigation was to assess the effect of nisoldipine in a conscious pig model of repetitive ischemia, and to determine whether the drug exerts direct cardioprotection independent of hemodynamic changes. A total of 33 conscious pigs were used. Pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, and were randomly assigned to a treated group (n = 11), in which nisoldipine was infused at a rate of 0.5 microgram/kg/min from 15 min before the first coronary occlusion till 30 min after the last reperfusion, and a control group (n = 12), which received vehicle. Results showed that there were no significant differences between the two groups with respect to ischemic bed size or hemodynamic variables throughout the experiment. Collateral blood flow to the ischemic regions was virtually nil in both groups. During the sequence of coronary occlusions, systolic thickening fraction in the ischemic region decreased similarly in the two groups. After the 10th reperfusion, however, the recovery of wall thickening was markedly enhanced in treated compared to control pigs, with the differences being statistically significant at 5, 15, and 30 min and 1, 3, 4 and 5 h. The total deficit of wall thickening after the 10th reperfusion (an integrative assessment of post-ischemic dysfunction) was 51% less in the treated compared with the control group (P < 0.001). This study demonstrates that nisoldipine markedly attenuates myocardial stunning after multiple ischemic episodes in conscious pigs, the improvement is evident immediately after the end of the ischemic episodes and is sustained throughout the recovery phase. This beneficial effect is independent of any favourable hemodynamic changes, and therefore indicates a direct cardioprotective action of nisoldipine.
J Mol Cell Cardiol 1996 Apr
PMID:Nisoldipine attenuates myocardial stunning induced by multiple coronary occlusions in conscious pigs and this effect is independent of changes in hemodynamics or coronary blood flow. 873 94

A non-contracting scar following myocardial infarction can adversely affect ventricular topography and hemodynamic function. Gene transfer has the potential to prevent or alter such pathophysiological processes. Normal myocardium is a proven target for delivery of DNA or viral vectors but the potential for gene therapy in ischemic myocardium has not been evaluated. In an initial series of experiments, we determined whether the direct injection of reporter genes into hearts subjected to coronary artery occlusion followed by reperfusion could result in gene expression comparable to the levels observed in non-occluded normal hearts. Anesthetized rats were subjected to 15 min or 60 min of proximal coronary occlusion or sham operation. Luciferase gene under the control of the Rous sarcoma virus promoter was injected directly into the anterior left wall. At 1 week, high expression of luciferase was observed in both the ischemic/reperfused and non-ischemic tissue. Thus DNA transfer by direct injection is possible after ischemic injury and uptake and expression are not impaired. In a second series of experiments, myocardial infarcts in dogs were injected with a beta-galactosidase expressing retroviral vector. LNPOZ. Six to 11 days later frozen sections revealed macroscopically visible expression of beta-galactosidase activity. Not only can foreign genes be taken up by direct injection of DNA or retroviruses into ischemic/reperfused myocardium but they can be transcribed and the protein synthetic machinery of the injured cells can produce recombinant polypeptides that retain enzymatic activity. These results open the way for the investigation of gene therapy in models of ischemia.
J Mol Cell Cardiol 1996 Jan
PMID:Ischemic/reperfused myocardium can express recombinant protein following direct DNA or retroviral injection. 874 21

The purpose of this study was to evaluate the protective effect of a new endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three groups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion. First group of rabbits (n = 6) were treated with 0.35 ml vehicle (40% propylene glycol, 10% ethanol in water). The second and third group of rabbits (n = 6-8) were treated with MLA (35 micrograms/kg, i.v.) 12 and 24 hours prior to ischemia and reperfusion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion demonstrated significantly reduced infarct size (12.5 +/- 1.7 and 14.7 +/- 2.1% for 12 and 24 h) when compared with vehicle control (40.4 +/- 8.6%, mean +/- S.E.M, p < 0.05). No significant differences in the infarct size was observed between the 12 and 24 h MLA treated groups. The area at risk was not significantly different between the three groups. Baseline values of heart rate, systolic and diastolic blood pressure were not significantly different between the control and MLA treated groups. However, the systolic as well as diastolic blood pressure during reperfusion were significantly lower in rabbits treated with MLA. Western blot analysis of the protein extracts of the hearts (n = 2/group) demonstrated no increase in the expression of the inducible form of HSP 70 following treatment with MLA. We conclude that MLA has significant anti-infarct effect in rabbit which is not mediated by the cardioprotective protein HSP 70. The anti-infarct effect of this drug is superior to the reported protective effects of delayed ischemic or heat stress preconditioning. We hypothesize that the pharmacologic preconditioning afforded by MLA is accomplished via a unique pathway that bypasses the usual intracellular signaling pathways which lead to the myocardial protection with the expression of heat shock proteins.
Mol Cell Biochem 1996 Jun 07
PMID:Monophosphoryl lipid A induces pharmacologic 'preconditioning' in rabbit hearts without concomitant expression of 70-kDa heat shock protein. 881 12

This study tested the hypothesis that endogenous opioids are involved in the infarct limitation of myocardial ischemic preconditioning (IP). Blockade of IP-induced infarct limitation by (-)naloxone hydrochloride (-NAL) or its receptor-inactive stereoisomer (+)naloxone (+NAL) was evaluated. Fifty-two pentobarbitone-anesthetized, open-chest rabbits underwent 30 min coronary artery occlusion and 180 min reperfusion. Treatment groups were: control (n = 9), i.p. (n = 8), -NAL (n = 9) and -NAL/i.p. (n = 12), or +NAL (n = 6) and +NAL/i.p. (n = 8). i.p. was elicited with 5 min regional ischemia, beginning 15 min before the 30 min coronary occlusion. -NAL or +NAL, 3 mg/kg i.v. bolus, was given 25 min before the 30 min coronary occlusion. Infarct size was assessed with tetrazolium and expressed as a percentage of area-at-risk. There were no significant intergroup differences of area-at-risk. IP resulted in marked infarct limitation compared to control (control, 32.9 +/- 7.6% v i.p., 5.8 +/- 4.5%; P = 0.04). Neither -NAL nor +NAL alone altered infarct size compared to control, but -NAL did block the infarct limitation of i.p. (-NAL, 31.4 +/- 6.7% v -NAL/i.p., 24.3 +/- 6.2%) whereas +NAL did not (+NAL, 40.5 +/- 5.0% v +NAL/i.p., 13.7 +/- 3.6%; P = 0.02). In conclusion, naloxone blockade of i.p.-induced cardioprotection is stereospecific and therefore likely to be opioid receptor-mediated.
J Mol Cell Cardiol 1996 Sep
PMID:Naloxone blockade of myocardial ischemic preconditioning is stereoselective. 889 48

The protection of ischemic preconditioning (PC) appears to be triggered by activation of receptors which couple to protein kinase C (PKC) during the brief ischemia. Previous experiments, however, suggest that phosphorylation of PKC's substrates is not required for the myocytes to enter the preconditioned state. Because of the fundamental importance of this observation, the present study was designed to stringently test when phosphorylation must occur during a PC protocol. We used an in vitro rabbit heart which permitted precise control of the timing of exposure to staurosporine (STA), a reversible blocker of PKC's kinase activity. In control hearts a 30-min regional coronary occlusion followed by 2 h of reperfusion resulted in 31.4 +/- 1.5% infarction of the region at risk, and STA (100 nM) had little effect. PC with 5 min of global ischemia and 10 min of reperfusion reduced infarction to 11.4% (P < 0.01 v control). STA starting 5 min before and ending 5 min after the 5-min PC ischemia did not block protection (14.1 +/- 1.7% infarction, P < 0.01 v control). When the PC protocol was changed to 5 min ischemia/20 min reperfusion, STA still could not block protection even though the infusion continued for 15 min after the PC ischemia. However, when a 15-min STA infusion was initiated 5 min before the 30-min ischemic period. PC's protection was totally blocked. Moreover this late infusion of STA continued to block protection even when the PC stimulus was amplified by three cycles of 5-min ischemia/10-min reperfusion. These observations indicate that kinase activity is not required to put the rabbit heart into a preconditioned state suggesting that some process upstream of PKC's kinase is responsible for the triggering and memory of PC.
J Mol Cell Cardiol 1997 Mar
PMID:Protection of ischemic preconditioning is dependent upon a critical timing sequence of protein kinase C activation. 915 60

Pretreatment with monophosphoryl lipid A (MLA) can pharmacologically mimic the second window of ischemic preconditioning (SWOP) to protect the heart from prolonged ischemia and reperfusion injury. Based on the delayed time course for development of MLA associated cardioprotection, this study was designed to test if MLA's cardioprotective effect is mediated by signalling through production of inducible nitric oxide synthase (iNOS), a proposed effector of SWOP. Rabbits were assigned to one of four groups: (1) vehicle control; (2) MLA: (3) vehicle+aminoguanidine (AMG) control; or (4) MLA+AMG. Monophosphoryl lipid A (35 micrograms/kg) or vehicle was given intravenously 24 h before ischemia. The selective iNOS inhibitor AMG (300 mg/ kg) was injected subcutaneously 1 h before ischemia. All rabbits experienced 30 min coronary artery occlusion followed by 3 h of reperfusion. Infarct size was measured by triphenyltetrazolium chloride (TTC) staining. followed by 3 h of reperfusion. Infarct size was measured by triphenyltetrazolium chloride (TTC) staining. Myeloperoxidase activity, an index of neutrophil infiltration, was also quantified in heart tissue collected from the post-ischemic viable border zone surrounding the infarct area. MLA pretreatment significantly reduced infarct size and neutrophil infiltration in rabbit hearts compared to control (P < 0.05). Inhibition of iNOS activity by AMG abolished the infarct size reductive effect of MLA. Aminoguanidine also blocked the ability of MLA to significantly reduce neutrophil infiltration. Although measurement of iNOS activity did not show induction of the enzyme in normal myocardial tissue 24 h after MLA pretreatment, an increase in iNOS activity in ischemic tissue relative to non-ischemic tissue was found after either 15 or 30 min of coronary occlusion in MLA treated rabbits. These results suggest that MLA pretreatment may enhance iNOS enzyme activity by MLA during ischemia which may be responsible for the observed cardioprotection.
J Mol Cell Cardiol 1997 Jun
PMID:Role of inducible nitric oxide synthase in pharmacological "preconditioning" with monophosphoryl lipid A. 922 Mar 42

To determine whether epicardial temperature varies among anesthetised, open-chest dogs, and, if so, whether such variation has a measurable effect on myocardial infarct size, 35 open-chest mongrel dogs underwent 60 min of circumflex coronary artery occlusion and 3 h of reperfusion. Infarct size was measured using triphenyl tetrazolium chloride (TTC) macrochemistry. Known predictors of infarct size including area-at-risk (AAR) and collateral blood flow (CBF) were measured. Epicardial temperature was monitored using a temperature probe placed in the pericardial space adjacent to the posterior surface of the heart. In each individual dog, epicardial temperature was nearly constant throughout the period of coronary occlusion. Amongst dogs, however, epicardial temperature ranged from 35.5-41.0 degrees C. By multiple regression analysis, infarct size was better predicted by the combination of temperature and CBF than by CBF alone. "Low-T" (35.5-38.0 degrees C, n = 17) and "high-T" (38.1-41.0 degrees C, n = 18) subgroups were compared by analysis of covariance (ANCOVA), using infarct size as the dependent variable and CBF as the independent variable. Following adjustment of infarct size for CBF, infarct size in the low-T subgroup was only 53% v that in the high-T subgroup (16.9 +/- 2.7% v 31.9 +/-5.0% of AAR, P < 0.001). Thus, in open-chest dogs, relatively minor variation in epicardial temperature had major effects on myocardial infarct size. We conclude that myocardial temperature is an independent predictor of infarct size in dogs. Although such variation could confound studies of the therapeutic efficacy of proposed cardioprotective interventions, controlling for temperature variation in such studies should reduce the likelihood of false positive or negative results.
J Mol Cell Cardiol 1997 Jun
PMID:Epicardial temperature is a major predictor of myocardial infarct size in dogs. 922 Mar 43

We have previously reported a delayed or "second window of protection" against infarction 24-72 h after ischemic preconditioning in the rabbit. This phenomenon has also been associated with the protein kinase C signalling pathway. In the present study, we expanded our investigation to ascertain whether protein tyrosine kinase was in any way associated with this phenomenon in the rabbit heart. We found that 48 h after ischemic preconditioning with 4x5 min coronary occlusions the percentage of myocardium infarcting within the risk zone following a 30-min coronary occlusion and 120-min reperfusion (I/R) was reduced from 39. 6+/-3.3% to 18.0+/-3.7% (P<0.01). However, an i.v. bolus administration of genistein (5 mg/kg), a tyrosine kinase inhibitor, 5 min before ischemic preconditioning stimulus, abolished this protection (I/R=39.0+/-3.4%). Genistein per se had no significant effect on infarction 48 h later. Risk zone volume after coronary ligation was not significantly different between intervention groups. There were no differences in hemodynamic parameters between groups throughout the experimental period. We conclude that the second window of protection, 48 h after preconditioning, is mediated by tyrosine kinase activation in the rabbit heart.
J Mol Cell Cardiol 1997 Jul
PMID:Genistein, a tyrosine kinase inhibitor, blocks the "second window of protection" 48 h after ischemic preconditioning in the rabbit. 923 42

Previous work suggests that delayed protection against infarction following ischaemic preconditioning of rabbit myocardium may involve the activation of protein kinase C (PKC). Preconditioning in the presence of chelerythrine, an inhibitor of PKC, abolished the late anti-infarct effect of preconditioning. In the studies described here, we tested the hypothesis that direct PKC activation with an analogue of diacylglycerol, the physiological activator of PKC, would invoke an adaptive mechanism leading to enhanced myocardial tolerance to ischaemia 24 h later. Rabbits were treated with i.v. injections of 1,2-dioctanoyl-sn-glycerol (DiC8) 5 mg/kg or 15 mg/kg or an equivalent volume of vehicle solution. Twenty-four h after pretreatment, the animals were anaesthetised and underwent 30 min coronary artery occlusion with 120 min reperfusion. Infarct size was determined by triphenyltetrazolium staining. In vehicle pretreated rabbits, infarct-risk zone ratio was 32.8+/-2.6%. Pretreatment with DiC8 5 mg/kg did not significantly affect infarct size (26.3+/-4.0%), but pretreatment with DiC8 15 mg/kg resulted in a marked reduction in infarct size (18.0+/-3.4%, P<0.05, 1-way ANOVA). Reduction in infarct size with the higher dose of DiC8 was independent of myocardial risk zone size and systemic haemodynamic parameters during coronary occlusion. The haemodynamic effects of acute administration of DiC8 15 mg/kg were examined in a separate cohort of pentobarbitone-anaesthetised rabbits. The compound was found not to affect systolic blood pressure or heart rate under these conditions. We examined the possibility that increased ischaemic tolerance might be due to induction of the 27 and 72 kDa heat shock proteins (hsp27 and hsp70i) which are known to be cytoprotective and are upregulated by ischaemia and other stressful stimuli. Western blot analysis of left ventricular tissue revealed that neither protein was induced 24 h after treatment with DiC8 15 mg/kg. Thus, infarct limitation 24 h after DiC8 treatment did not appear to be due to increased tissue content of these proteins. The mechanisms of DiC8-induced delayed myocardial protection remain unclear. However, these data are compatible with the hypothesis that activation of PKC isoenzymes is an important intermediate signal of sub-acute cellular adaptation, and results in enhanced tolerance to ischaemia-reperfusion injury in myocardium many hours later.
J Mol Cell Cardiol 1997 Jul
PMID:Attenuation of myocardial ischaemic injury 24 h after diacylglycerol treatment in vivo. 923 50


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