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Global regulatory functions of Oaf1p and Pip2p (Oaf2p), transcription factors that regulate genes encoding peroxisomal proteins in Saccharomyces cerevisiae.

Two transcription factors, Oaf1p and Pip2p (Oaf2p), are key components in the pathway by which several Saccharomyces cerevisiae genes encoding peroxisomal proteins are activated in the presence of a fatty acid such as oleate. By searching the S. cerevisiae genomic database for the consensus sequence that acts as a target for these transcription factors, we identified 40 genes that contain a putative Oaf1p-Pip2p binding site in their promoter region. Quantitative Northern analysis confirmed that the expression of 22 of the genes identified is induced by oleate and that either one or both of these transcription factors are required for the activation. In addition to known peroxisomal proteins, the regulated genes encode novel peroxisomal proteins, a mitochondrial protein, and proteins of unknown location and function. We demonstrate that Oaf1p regulates certain genes in the absence of Pip2p and that both of these transcription factors play a role in maintaining the glucose-repressed state of one gene. Furthermore, we provide evidence that the defined consensus binding site is not required for the regulation of certain oleate-responsive genes.

ATP-Binding Cassette Transporters

Differences in cardioprotective efficacy of adrenergic receptor antagonists and Ca2+ channel antagonists in an animal model of dilated cardiomyopathy. Effects on gross morphology, global cardiac function, and twitch force.

Turkey poults fed furazolidone (Fz) in high concentrations (700 ppm) develop dilated cardiomyopathy (Fz-DCM). We tested whether five cardioactive agents were cardioprotective in this model of heart failure, ie, whether they prevented dilatation and wall thinning and improved contractile performance. We compared the effects of chronic administration of a beta 1-selective and a nonselective beta-receptor antagonist, an alpha-receptor antagonist, and two Ca2+ channel antagonists in the presence of Fz administration. The greatest cardioprotection was found with treatment with either propranolol or nifedipine. At the gross morphological level, the effect of propranolol (a nonselective beta-adrenergic antagonist) was greater than the effect of atenolol (a selective beta 1-adrenergic antagonist), and the effect of nifedipine was greater than that of verapamil (Ca2+ channel antagonists), with all agents more cardioprotective than phenoxybenzamine (an alpha 1-adrenergic > alpha 2-adrenergic antagonist). Differences in cardioprotective efficacy of each agent increased with increased concentration. These data indicate that the dose and choice of a specific type of Ca2+ channel antagonist or beta-receptor antagonist might be important in the treatment of dilated cardiomyopathy. All agents that were cardioprotective caused similar functional improvements at both the whole heart and isolated muscle levels. Compared with control animals, Fz-DCM animals showed a significant reduction in peak left ventricular (LV) developed pressure (92 +/- 17 versus 143 +/- 24 mm Hg, P < .05), +dP/dt (1151 +/- 219 versus 2454 +/- 549 mm Hg/s), and -dP/dt (1128 +/- 291 versus 1875 +/- 396 mm Hg/s), with a significant increase in LV end-diastolic volumes (2.8 +/- 0.7 versus 0.16 +/- 0.1 mL for control animals, P < .05). In contradistinction, LV + dP/dt and -dP/dt values for animals receiving Fz plus a cardioactive agent that demonstrated cardioprotection were not significantly different from control values. Peak LV developed pressures were also similar for Fz animals receiving an agent that demonstrated cardioprotection and control animals not receiving any pharmacologic agent. Isolated muscles from Fz-DCM animals as well as animals receiving Fz plus cardioprotective pharmacologic agents responded normally with regard to increasing extracellular Ca2+ concentrations. Peak twitch forces were greater for animals receiving cardioprotective agents plus Fz than control animals not receiving any pharmacologic agents or Fz alone. At higher stimulation rates, Fz-DCM muscles demonstrated a significantly reduced peak twitch force (4 +/- 0.5 versus 1.5 +/- 0.4 g/mm2 for control muscles versus Fz-DCM muscles, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Effect of mild hyperthermia on recovery of metabolic function after global cerebral ischemia in cats.

We investigated the effect of mild whole-body hyperthermia before and after 16 minutes of global cerebral ischemia on metabolic recovery during recirculation in cats using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Hyperthermia (temperature 40.6 +/- 0.2 degrees C) was induced greater than or equal to 1 hour before ischemia and was maintained during 1.5-2 hours of recirculation in nine cats; four cats were subjected to hyperthermia without cerebral ischemia, six to hyperthermia during recirculation (after return of intracellular pH to preischemic values), and 14 to normothermic ischemia and recirculation. Our data indicate that preischemic hyperthermia results in an intracellular cerebral pH during recirculation significantly lower than that in normothermic cats. In hyperthermic cats beta-ATP and phosphocreatine (PCr) concentrations and the ratio of PCr to inorganic phosphate failed to return to preischemic levels during recirculation in contrast to normothermic cats. Hyperthermia without ischemia and hyperthermia during recirculation had no significant effect on intracellular pH. Thus, preischemic hyperthermia has a detrimental effect on metabolic recovery after transient global cerebral ischemia.

Acidosis

[Left ventricular global and segmental function in pure mitral valve prolapse with poor tolerance for exertion].

Poor effort tolerance is observed in a small percentage of cases of idiopathic mitral valve prolapse (IMVP). The aim of this study was to assess the possible left ventricular dysfunction in such cases, responsible for poor effort tolerance. Left ventricular function and segmental wall motion were studied retrospectively in a group of 17 patients with IMVP. The patients, average age 53 +/- 12 years, had poor effort tolerance (ST segment depression of 2 to 4 mm in 15 cases, drop in blood pressure in 6 cases) justifying catheter and angiographic studies. All patients had IMVP confirmed on RAO left ventriculography. There was no associated mitral regurgitation or coronary artery disease. Left ventricular function was studied by parameters of global function (systolic and diastolic parameters, volume measurements) and by a quantitative study of segmental wall contraction. The method used for studying regional wall motion was an application of the Stanford method in which segmental shortening is studied over all the endocavitary contour of the LV during an angiographic cycle filmed at 50 frames/second in the RAO projection. The time and velocity amplitudes of wall motion were measured during systole and diastole. The same methodology was applied to 21 normal control subjects. The results showed abnormal volumic compliance and wall motion in the IMVP group. Asynergy was mainly confined to the antero-lateral wall of the LV. The amplitude of contraction was generally normal but the contraction was slower and finished earlier. In the same zone, relaxation was abnormally early and lasted longer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

[Global ventricular function and synchronism of contraction during and after exertion].

Phase analysis and ejection fraction (EF) of the left ventricle were obtained by radionuclide angiography in 53 patients at rest, during submaximal exercise and 3-8 minutes after exercise. The standard deviation of the peak of the histogram of phases (SDP) was used as an index of the synchronicity of regional contraction. The material comprised 13 sportsmen and 40 patients who underwent coronarography, 12 of whom had normal coronaries and 28 significant lesions. EF, while comparable in the three groups at rest, increased significantly on effort in normals and did not change in patients with coronary disease. At rest SDP was higher in coronary patients than in normals (p less than 0.01), and during exercise, it increased, but decreased in normals (p less than 0.01). After exercise, mean EF decreased in comparison with exercise in normals (p less than 0.01), while the opposite was the case in coronary patients. Normals had lower SDP values in the post-exercise period than at rest; on the other hand, SDP of coronary patients was significantly higher in the post-exercise period than at rest (p less than 0.001). Phase analysis during, and particularly after, exercise was found to be superior to EF in detecting ischemic left-ventricular dysfunction, and should be used in conjunction with EF to evaluate patients suspect for coronary disease.

Adult

[Radionuclide ventriculography. II. Clinical results--parameters of global ventricular function (author's transl)].

The ejection fraction as determined by gated blood pool studies was compared with the ejection fraction as evaluated by the following conventional methods: 1) biplane cineangiography employing the Simpson rule. Correlation was r = 0.805 (n = 25); 2) the same patients using the area-length method (r = 0.88, n = 25); 3) monoplane cineangiography using the method of Greene et al. (5) (r = 0.86, n = 35). In 20 patients the maximal contraction velocity as evaluated by radionuclide ventriculography was compared with the mean systolic ejection rate. The observed correlation was weak (r = 0.62, n = 20); however, it should be noted that the radionuclide method determines the maximum contraction velocity whereas cinceangiography measures an average value over the whole systole.

Cineangiography

[Motion of the posterior wall in the m-mode echocardiogram - a parameter of global left function (author's transl)].

The cardiac output was determined by thermodilution in 42 patients during heart catheterization and compared to the amplitude of the posterior aortic wall in the m-mode echocardiogram. The amplitude of the posterior aortic wall was measured at the time of the closure of the aortic cusps (KS) and at the time the maximal excursion of the posterior aortic wall occurred (GA). Both parameters correlated strongly to the cardia output (r = 0.84, KS; r = 0.76, GA) and to the forward stroke volume (r = 0.81, KS; r = 0.73, GA). Thus, the amplitude of the posterior aortic wall in the m-mode echocardiogram is a useful parameter in predicting left ventricular function especially in those patients, in whom determination of left ventricular function from the m-mode echocardiogram is limited due to left ventricular asynergy.

Aorta

Alterations in regional myocardial function after heterogeneous cardioplegia.

Coronary stenoses lead to heterogeneous delivery of cardioplegic solution during cardiac operations. This situation was simulated by occlusion of the circumflex artery during cardioplegic infusion in canine right heart bypass preparations. Regional myocardial function (systolic shortening by sonomicrometer) was often diminished, despite preservation of global function. The correlation between recovery of circumflex regional function and recovery of stroke work or dP/dt (at constant aortic pressure, heart rate, and left atrial pressure) was poor (r = 0.17 and 0.07). The response of damaged regions to hemodynamic manipulations was studied. Increases in afterload after arrest did not lead to further deterioration of damaged regions. Volume loading (cardiac output 2 to 5 L/min) improved regional function even in severely damaged, bulging regions (p less than 0.05). Regional distensibility (delta length/delta left atrial pressure) decreased by 41% (p less than 0.02) in regions with poor protection and by 22% (p less than 0.01) in regions with good cardioplegic protection. There was also an increase in resting length (p less than 0.001) in both circumstances (5.2% and 3.7%). These changes in diastolic properties have not always been apparent in other experimental studies with less precise hemodynamic control. Heterogeneous cardioplegia causes heterogeneous changes in both diastolic distensibility and systolic function. These changes are poorly detected by examination of global ventricular function.

Animals

Myocardial preservation: a comparison of oxygenated crystalloid and blood cardioplegia.

The purpose of this experiment was to compare myocardial protective effect after global ischemia using oxygenated crystalloid (CCcO2) and an oxygenated blood (BCcO2) cardioplegic solutions. Post-ischemic ventricular performance was studied in 2 equal (n = 7) groups of dogs subjected to 120 min of global ischemia induced at average myocardial temperatures of 8 degrees C in the CCcO2 group and 18 degrees C in the BCcO2 group. Left ventricular (LV) function included analysis of LV systolic function (global and regional function), LV diastolic function (chamber and myocardial stiffness) and LV relaxation was measured by sonomicrometry and Millar micrometers. Data were processed with a Dec PDP-11/23 computer. In vitro oxygen content (Vol%) measured 3.2 +/- 1.0 (CCcO2) and 9.5 +/- 0.3 (BCcO2). Percent recoveries of LV global function (LVSP, loop area, % shortening, LV dp/dt, mean VCF and E max) in the CCcO2 group were approximately the same as those in the BCcO2 group. There were no significant differences in LV regional function (loop area and % shortening) after ischemia between the two groups. The chamber and myocardial stiffness after ischemia in the CCcO2 group were almost the same as the baseline values. Values in the BCcO2 group were reduced significantly compared to the baseline level. There were significant differences in post-ischemic chamber and myocardial stiffness between the two groups. Post-ischemic maximum negative LV dp/dt in both groups decreased significantly compared to the baseline values. However, the time constant and diastolic interval after ischemia in both groups were approximately the same as the baseline values. We conclude that there were no significant differences in myocardial protective effect between the CCcO2 and BCcO2 groups, and both methods preserved the ischemic myocardium well.

Animals

Preservation of regional and global left ventricular function by intracoronary infusion with oxygenated fluorocarbon emulsion Therox in dogs.

We tested the oxygen transport and delivery capacity of the novel perfluorocarbon emulsion, Therox (F44E, 1,2-bis-perfluorobutyl-ethylene) by comparing left ventricular regional and global function in dogs during perfusion of the left anterior descending coronary artery (LAD) with oxygenated Krebs buffer and oxygenated Therox emulsion (20% w/v) at 20 ml/min for two separate 3 min periods. During LAD perfusion with oxygenated Krebs buffer, complete loss of systolic wall thickening in the LAD perfusion area was observed, dP/dt was significantly reduced and left ventricular end-diastolic pressure (LVEDP) was increased. In contrast, LAD perfusion with oxygenated Therox maintained regional wall thickening at 60-70% of control and completely preserved global function as measured by dP/dt and LVEDP. Thus, Therox is an effective oxygen carrier in this animal model.

Animals