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Query: UNIPROT:P06889 (Mol)
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Low flow ischemia with stable hemodynamic function can result in partial metabolic recovery characterized by an increase in phosphocreatine (PCr). Prior data suggest that glycolytic production of adenosine triphosphate (ATP) may be critical for this recovery and that the ATP produced by oxidative phosphorylation alone may be insufficient. This study tested the hypotheses that, during moderate low flow ischemia, (a) metabolic recovery is dependent on glycolytic production of ATP, and, therefore, (b) a mitochondrial substrate such as pyruvate alone is inadequate to allow metabolic recovery. High energy phosphates, pH, and lactate release were measured during 2 h of moderate low flow ischemia. Hearts were perfused with either a glycolytic plus mitochondrial substrate (glucose, insulin and pyruvate) or a mitochondrial substrate alone (pyruvate). Flow reductions required to reduce PCr by approximately 8% resulted in stable and equal reductions of rate-pressure product in each group. PCr recovered fully during the ischemic period in control hearts with glycolytic substrate, associated with preservation of normal end-diastolic pressure, and increased lactate release during the first hour of ischemia. Reperfusion of these hearts restored hemodynamic function and increased PCr above baseline values. In contrast, the use of pyruvate alone as a substrate resulted in a progressive fall of PCr during ischemia, increased end-diastolic pressure, and no significant increase in lactate release. Reperfusion in these hearts restored hemodynamic function, but did not result in normalization of PCr. Both groups had significant reductions in ATP during ischemia. Recovery of PCr during ongoing moderate low flow ischemia is observed in the presence of mixed glycolytic and mitochondrial substrates (glucose, insulin and pyruvate) but is not observed with pyruvate as a sole mitochondrial substrate. These data support a critical role for glycolytic flux under these conditions, suggesting that ATP generated solely by oxidative phosphorylation is not sufficient to promote metabolic recovery or maintain diastolic function during moderate low flow ischemia.
J Mol Cell Cardiol 1995 Oct
PMID:Requirement of glycolytic substrate for metabolic recovery during moderate low flow ischemia. 857 33

Reduced glutathione (GSH) is a major myocardial antioxidant. Since reperfusion phenomena such as ventricular fibrillation (VF) are associated with oxygen free radical production during ischaemia, myocardial GSH depletion might be expected to increase susceptibility to such phenomena. This possibility was tested in isolated rat hearts using diethylmaleate (DEM) or L-buthionine-SR-sulfoximine (BSO) to deplete myocardial GSH. High dose DEM (860 mg/kg) depleted myocardial GSH from a control mean of 7.64 +/- 0.73 to 3.18 +/- 0.56, low dose DEM (215 mg/kg) to 4.29 +/- 0.53 nmol/mg protein and BSO (4 mmol/kg) from a control mean of 6.94 +/- 0.54 to 2.18 +/- 0.14 nmol/mg protein. Hearts were perfused in the Langendorff mode at 37 degrees C with bicarbonate buffer (K+ = 4.3 mM). Regional ischaemia was induced for 5, 8.5, 10, 20 or 40 min (DEM groups: n = 10/treatment/time point) or 8.5 min only (BSO groups: n = 10/treatment) then hearts were reperfused for 5 min. Reperfusion VF incidence showed a classical "bell-shaped" curve, but there was no difference in VF incidence, VF time-to-onset, arrhythmia duration and "arrhythmia scores" between GSH-depleted and control hearts. Depleting myocardial GSH is not proarrhythmic for reperfusion-induced arrhythmias. It would appear GSH is not significantly involved in protecting against the oxidant stress of reperfusion, or conversely that the reserve of this redox system is so high only severe depletion might show an effect.
J Mol Cell Cardiol 1996 Apr
PMID:Ventricular arrhythmias induced by ischaemia-reperfusion are unaffected by myocardial glutathione depletion. 873 96

Following left coronary artery ligation in the rat, markedly increased angiotensin converting enzyme (ACE) binding appears at the site of myocardial infarction (MI). This is also the case in fibrosed visceral pericardium that follows pericardiotomy alone (without MI). Immunohistochemical ACE labeling, using a monoclonal antibody, indicates fibroblast-like calls express ACE at each of these sites of tissue repair. It is unknown, however, whether these cells are phenotypically transformed fibroblasts containing alpha-smooth muscle actin (i.e. myofibroblasts). This study was therefore undertaken to determine whether myofibroblasts appear at the site of MI and pericardial fibrosis and their relationship to ACE expression. MI was created by left coronary artery ligation. Fibrosis of the visceral pericardium was induced by pericardiotomy alone. Hearts were studied on postoperative day 3, week 1, 2, 4 and 8. In serial sections of the same heart: immunohistochemistry (anti alpha-smooth muscle actin antibody and monoclonal ACE antibody, 9B9) was used to detect myofibroblasts and cells expressing ACE, respectively. We found that at sites of MI and pericardial fibrosis, myofibroblasts began to appear on day 3 and became abundant at week 1, 2, 4 and remained in these repairing sites for at least 8 weeks. Myofibroblasts at sites of MI and pericardial fibrosis are positively labeled by ACE antibody. Thus in these models of tissue repair involving either MI or pericardial fibrosis, myofibroblasts are associated with ACE expression. These findings suggest that myofibroblast ACE may play a role in the fibrogenic response of tissue repair in the rat myocardium by regulating local concentrations of substances involved in healing and matrix remodeling.
J Mol Cell Cardiol 1996 May
PMID:Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart. 876 25

To test the authors' hypothesis that cellular antioxidant enzymes constitute a cellular defense against acute stress, myocardial ischemia reperfusion injury in transgenic mice overexpressing the cellular glutathione peroxidase (GSHPx-1) was studied. Transgenic mice were generated using the entire mouse GSHPx-1 gene including approximately 2.0 kb 5'flanking sequence. A 400% increase of GSHPx activity was found in the hearts of transgenic mice compared with non-transgenic controls. Isolated perfused hearts were prepared from two groups of mice: transgenic overexpressed; non-transgenic controls. Hearts were perfused by Langendorff mode, and after 10 min of stabilization subjected to 30 min of ischemia followed by 20 min of reperfusion. In addition, a group of hearts were perfused for 50 min without subjecting them to ischemia and reperfusion to demonstrate the stability of heart preparation. Transgenic mouse hearts demonstrated significantly improved recovery of contractile force and the rate of contraction, compared to non-transgenic control mouse hearts. The infarct size was also lower in transgenic mouse hearts compared to those of non-transgenic controls. In concert, following ischemia, release of creatine kinase from the transgenic hearts was significantly lower than the control group. The results of this study indicate that increased GSHPx-1 expression renders the heart more resistant to myocardial ischemia reperfusion injury.
J Mol Cell Cardiol 1996 Aug
PMID:Transgenic mice overexpressing glutathione peroxidase are resistant to myocardial ischemia reperfusion injury. 887 85

Elevation of cell iron content was produced by use of a lipophilic iron ligand, 8-hydroxyquinoline (HQ), capable of transferring catalytically active iron into cells. The Fe(3+)-HQ complex labeled with 59Fe was avidly taken up by isolated perfused hearts contrary to the hydrophilic complex Fe(3+)-citrate. Hearts perfused in aerobic conditions with Krebs-Henseleit buffer were exposed for 15 min to the iron complexes, Fe(3+)-HQ (5 microM/10 microM and 10 microM/20 microM), or Fe(3+)-citrate (10 microM), and then perfused for 30 min with normal buffer. Exposure to the high dose of Fe(3+)-HQ (10 microM/20 microM) resulted in early and irreversible decreases in coronary flow and heart rate (-48% and -33%, respectively), initial increases followed by decreases in left ventricular systolic pressure and +dP/dt, and increase in left ventricular end-diastolic pressure (+80%). The low dose of Fe(3+)-HQ (5 microM/10 microM) mimicked with a lower magnitude the effects of the high dose, whereas Fe(3+)-citrate had no effects on cardiac parameters. Only hearts exposed to the high dose of Fe(3+)-HQ exhibited a significant increase (+60%) in thiobarbituric acid-reactive substance level, an index of lipid peroxidation. The production of hydroxyl radicals was investigated by measuring 2,3-dihydroxybenzoic acid level in the coronary effluent after addition of salicylic acid (1 mM) in the perfusate. An immediate and high increase (x6) was seen during heart exposure to Fe(3+)-HQ (10 microM/20 microM) and to Fe(3+)-citrate (10 microM). Considering Fe(3+)-citrate had no effect on cardiac function and lipid peroxidation it was concluded that this hydroxyl radical formation occurring in the extracellular space was not implicated in Fe(3+)-HQ-induced cardiac dysfunction. These results demonstrate the deleterious effect of increasing intracellular reactive iron level in non-ischemic hearts.
J Mol Cell Cardiol 1996 Aug
PMID:Effects of increasing intracellular reactive iron level on cardiac function and oxidative injury in the isolated rat heart. 887 86

The effects of treppe on left ventricular function in the isolated mouse heart perfused with physiological buffer or with erythrocyte-rich buffer were compared. Left ventricular systolic and diastolic pressures were measured in the isovolumically contracting (balloon in the left ventricle) mouse hearts. Hearts were isolated from 12 adult Swiss-Webster mice and perfused at constant pressure (approximately 85 mmHg) via the aorta. Perfusate consisted of non-recirculating oxygenated Krebs-Henseleit (KH) solution without or with washed cow red blood cells at a hematocrit of 20% (KH-RBC20). The measured ionized calcium concentration of the perfusates were adjusted to 2.2 mmol/l and the temperature held constant at 37 degrees C. Left ventricular systolic pressure, its derivative and diastolic pressures were recorded via a pressure transducer attached to a small latex balloon which was placed in the left ventricle through a left atrial incision. The balloon volume was adjusted to achieve an end-diastolic pressure of 4-8 mmHg. Left ventricular (LV) developed pressure averaged 111 +/- 4 (mean +/- S.E.M.) with KH alone and 108 +/- 4 mmHg with KH-RBC20 while the coronary flows were 3.1 +/- 0.18 and 0.95 +/- 0.15 ml/min respectively. In both KH solution alone and KH-RBC20, developed pressure remained relatively stable from 3 to 5 Hz while +/- dp/dt increased approximately 10% above values observed at 3 Hz. During KH perfusion with increasing stimulation rates, left ventricular pressure and +/- dP/dt, to a lesser extent, decreased while end-diastolic pressure markedly increased at stimulation rates higher than 5 Hz. However, KH-RBC20 perfusion prevented the marked increase in diastolic pressure with increasing stimulation rates (from 5 to 10 Hz). No significant difference in left ventricular developed pressure or +/dP/dt response to treppe were in evidence between groups. These results demonstrate that diastolic function of the isovolumically contracting mouse heart is sensitive to treppe and different techniques of perfusion. Buffer perfusion alone may limit accurate measurement of left ventricular diastolic properties and exacerbate changes in diastolic function, particularly under conditions of increased oxygen demand. The erythrocyte perfused mouse heart provides an in vitro model for determining cardiac function which is physiologically superior to buffer perfusion, and may be useful to investigators to assess gene influence on left ventricular function in genetically altered mice.
J Mol Cell Cardiol 1996 Aug
PMID:Effect of treppe on isovolumic function in the isolated blood-perfused mouse heart. 887 91

The contribution of mitochondrial free radical production towards the initiation of lipid peroxidation (LPO) and functional injury in the post-ischemic heart is unclear. Using the isolated rat heart model, the effects of the uncoupler of mitochondrial oxidative phosphorylation dinitrophenol (DNP, 50 microM final) on post-ischemic lipid peroxidation-derived free radical production and functional recovery were assessed. Hearts were subjected to 30 min total global ischemia followed by 15 min of reperfusion in the presence of DNP. As expected, DNP enhanced oxygen consumption before (11.3 +/- 0.9 mumol/min, p < 0.001) and during reperfusion (at 10 min: 7.9 +/- 0.7 mu umol/min), compared to the heart with control treatment (8.2 +/- 0.5 and 6.7 +/- 0.3, respectively). This effect was only associated with a higher incidence of ventricular tachycardia during reperfusion (80 vs. 50% for control treatment, p < 0.05). Electron spin resonance spectroscopy (ESR) and spin trapping with alpha-phenyl-tert-butylnitrone PBN-radical adducts (untreated: 6.4 +/- 1.0 nM, at 10 min) decreased in the presence of DNP (1.7 +/- 0.4 nM, p < 0.01). The radical concentration inversely correlated with myocardial oxygen consumption. Total liberation of free radical adducts during the initial 10 min of reperfusion was reduced by DNP (0.59 +/- 0.09 nmol, p < 0.01) compared to the respective control treatment (1.26 +/- 0.16 nmol). Similar effects, prevention of PBN adduct formation and unchanged viability in the presence of DNP, were obtained with endothelial cells during post-hypoxic reoxygenation. Since inhibition of mitochondrial phosphorylation can inhibit the formation of LPO-derived free radicals after an ischemic/hypoxic interval, mitochondria may represent an important source of free radicals capable of initiating lipid peroxidative injury during reperfusion/reoxygenation.
Mol Cell Biochem
PMID:Uncoupling of mitochondrial oxidative phosphorylation alters lipid peroxidation-derived free radical production but not recovery of postischemic rat hearts and post-hypoxic endothelial cells. 890 71

Earlier we reported that probucol treatment subsequent to the induction of diabetes can prevent diabetes-associated changes in myocardial antioxidants as well as function at 8 weeks. In this study, we examined the efficacy of probucol in the reversal of diabetes induced myocardial changes. Rats were made diabetic with a single injection of streptozotocin (65 mg/kg, i.v.). After 4 weeks of induction of diabetes, a group of animals was treated on alternate days with probucol (10 mg/kg i.p.), a known lipid lowering agent with antioxidant properties. At 8 weeks, there was a significant drop in the left ventricle (LVSP) and aortic systolic pressures (ASP) in the diabetic group. Hearts from these animals showed an increase in the thiobarbituric acid reacting substances (TBARS), indicating increased lipid peroxidation. This was accompanied by a decrease in the myocardial antioxidant enzymes activities, superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). Myocardial catalase activity in the diabetic group was higher. In the diabetic + probucol group both LVSP and ASP showed significant recovery. This was also accompanied by an improvement in SOD and GSHPx activities and there was further increase in the catalase activity. Levels of the TBARS was decreased in this group. These data provide evidence that diabetic cardiomyopathy is associated with an antioxidant deficit which can be reversed with probucol treatment. Improved cardiac function with probucol may be due to the recovery of antioxidants in the heart.
Mol Cell Biochem
PMID:Probucol treatment reverses antioxidant and functional deficit in diabetic cardiomyopathy. 890 84

Gene transfer as a therapeutic modality for the treatment of myocardial ischemia and/or infarction has been proposed as a revolutionary approach to improve collateral circulation, enhance myocardial viability and amplify healing. Our study was undertaken to assess the feasibility, efficiency, anatomic distribution, timing and localization of adenovirus-mediated gene transfer into the vicinity of infarcted myocardium in the adult mammalian heart. We induced myocardial infarction by subjecting rats to 60 min of coronary artery occlusion followed by sustained reperfusion. Gene transfer into the infarction area was performed using direct injection of a replication-defective adenovirus vector encoding the bacterial reporter gene, beta-galactosidase. A total of 5.0 x 10(9) plaque-forming units of virus was delivered into the left ventricular myocardium either immediately (n = 7) or at 7 (n = 6), 22 (n = 5) or 30 days (n = 5) after reperfusion of rat hearts. Control rats received either 50 microliters of saline 13 days after myocardial infarction (n = 2) or were not subjected to infarction and received Adenovirus carrying the beta-galactosidase gene as described above (n = 4). All rats were killed at 7 days after cardiac injection. Hearts were harvested, frozen and sectioned and stained for beta-galactosidase activity and with hematoxylin and eosin. Sections were evaluated by light microscopy. Relative beta-galactosidase activity was measured by digital planimetry and expressed as the ratio of the maximal area of beta-galactosidase staining relative to the total area of the section examined (% +/- S.E.M.). beta-galactosidase gene expression was limited mainly to viable myocytes at the border of the myocardial infarction. The area of transgene expression in the non-infarcted hearts (28 +/- 7%) was significantly higher (P = 0.02) than at any time point studied in infarcted tissues (3.4 +/- 1.2%, 1.4 +/- 1.0%, 2.8 +/- 0.8% and 3.4 +/- 0.9% at reperfusion and at 7, 22 and 30 days after myocardial infarction, respectively). Hearts injected 7 days after infarction had significantly less transgene activity (P = 0.03) with three of five samples displaying no macroscopically visible beta-gal activity. Following viral injection, an inflammatory response consisting of mononuclear cell infiltration was much less intense seven days following injection in non-infarcted control rat hearts than at any of the time points examined for infarcted hearts. Gene transfer into infarcted myocardium, while feasible, was limited by low transfection efficiency when compared to non-infarcted normal myocardium. Transgene expression in the infarcted myocardium appears restricted to residual cardiomyocytes in the periphery. Nevertheless, the ability to introduce genes into these viable peripheral cells might be a useful therapeutic strategy for enhancing neovascularization, collateral flow and healing.
J Mol Cell Cardiol 1996 Oct
PMID:Adenovirus-mediated gene transfer into infarcted myocardium: feasibility, timing, and location of expression. 893 Aug 2

Myocardial perfusion measurement with colored microspheres may become an alternative for radioactive microsphere techniques. We use and validate a spectrophotometric method that has been previously established for large animals in the isolated perfused rat heart. The perfusion system was adapted for use in a NMR microscope. Hearts were perfused with constant coronary flow that was adjusted to a coronary perfusion pressure of 100 mmHg. Homogeneous coronary inflow of microspheres was represented by equal distribution of microspheres of two different colors after simultaneous injection. Mean regional myocardial blood flow was 17.76 +/- 5.01 ml/min/g, mean wet heart weight was 1.13 +/- 0.34 g and mean global flow was 20.06 +/- 0.60 ml/min. Heart rate was 296 +/- 8.9 beats/min and left ventricular pressure was similar 5 min before (149.1 +/- 14.27 mmHg) and after (147.1 +/- 13.49 mmHg) microsphere injection. Microspheres of four colors that were injected sequentially, at various coronary flows, demonstrated linearity and reproducibility of the technique. A cumulative use of less than 90 000 microspheres showed no effect on hemodynamics especially on left ventricular pressure.
J Mol Cell Cardiol 1996 Mar
PMID:In vivo colored microspheres in the isolated rat heart for use in NMR. 901 40


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