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PubMed1985

5-Azacytidine permits gene activation in a previously noninducible cell type.

We previously reported that silent muscle genes in fibroblasts could be activated following fusion with muscle cells to form heterokaryons. This activation did not require changes in chromatin structure involving significant DNA synthesis. We report here that muscle gene activation was never observed when HeLa cells were used as the nonmuscle fusion partner. However, if HeLa cells were treated with 5-azacytidine (5-aza-CR) prior to fusion, muscle gene expression was induced in the heterokaryons. The genes for both an early (5.1H11 cell surface antigen) and a late (MM-creatine kinase) muscle function were activated, but were frequently not coordinately expressed. These results suggest that the expression of two muscle genes, which is usually sequential, is not interdependent. Furthermore, changes induced by 5-aza-CR, presumably in the level of DNA methylation, are required for muscle genes in HeLa cells to be expressed in response to putative trans-acting regulatory factor(s) present in muscle cells.

Animals↗
PubMed1995

Studies of hypoxemic/reoxygenation injury: without aortic clamping. IV. Role of the iron-catalyzed pathway: deferoxamine.

This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.

Alkadienes↗
PubMed2003

Isolation, characterization and nucleotide sequence of the muscle isoforms of creatine kinase from the Antarctic teleost Chaenocephalus aceratus.

Creatine kinase (CK) was isolated from the white muscle of the Antarctic icefish Chaenocephalus aceratus, which is deficient in glycolytic capacity. C. aceratus white myotomal creatine kinase (MMCK) displayed an apparent K(m) at 0.5 degrees C of 0.06 mM for ADP and 17 mM for Phosphocreatine. These K(m) values are similar to those reported for other vertebrate MMCKs at their physiologically relevant body temperatures. C. aceratus MMCK exhibited optimal activity at pH of 7.6-7.7 at 0.5 degrees C, in contrast to rabbit MMCK which had optimum activity at pH 6.2 at 30 degrees C. The apparent V(max) of C. aceratus MMCK at 0.5 degrees C is 94+/-4 S.D. (n=9) micromol ATP/min/mg (i.e. U/mg), which is comparable to rabbit MMCK assayed at 20 degrees C and 8-fold greater than rabbit MMCK measured at 0.5 degrees C. DEAE chromatography of C. aceratus white muscle CK resolved two distinct activity peaks. Cloning and sequencing of C. aceratus CK cDNAs confirmed that two muscle-specific isoforms of CK were expressed that were distinct from the mitochondrial and brain isoforms. Icefish MMCK was sensitive to transient temperature elevation, and the DEAE-fractionated forms were highly unstable. These results indicate that C. aceratus MMCK displays significant activity at physiological temperature and intracellular pH of icefish muscle that could contribute to sustaining energy charge during burst-swimming.

Adaptation, Physiological↗
PubMed1983

Kinetic properties and functional role of creatine phosphokinase in glycerinated muscle fibers--further evidence for compartmentation.

The following phenomena were observed when relative contraction and relaxation effects of ATP and creatine phosphate (CP) were studied in rabbit psoas muscle glycerinated fiber bundles containing native creatine phosphokinase (CPK) and ATPase activities: (1) nucleotide was absolutely necessary for contraction; (2) in the presence of a small amount of ADP (250 microM), physiological concentration of CP (10 mM) produced faster and stronger contraction and faster, more complete, relaxation than equimolar or higher concentrations of ATP; (3) if the nucleotide was in the form of ATP, the nucleotide Km for contraction was about 1.5 mM; (4) if the nucleotide was in the form of ADP, the nucleotide Km for contraction at physiological concentration of CP (10 mM) was 0.076 to 1.18 mM depending upon the order of addition of ADP and CP; (5) the apparent Km for CP for contraction was 2.67 mM independent of sequence of addition of ADP and CP.

Adenosine Diphosphate↗
PubMed1977

Detection of acute myocardial infarction by radioimmunoassay for creatine kinase MB.

A radioimmunoassay for the MB isoenzyme of creatine kinase (myocardial isoenzyme) has been developed based on an antibody to the B subunit. The antibody cross-reacts with MB but exhibits no cross-reactivity with MM C.K. even when present in 20 000 molar excess over MB C.K. unlabelled MB but not MM (up to 85 000 mI.U./ml) competitively displaces precipitable counts. This sensitive and specific radioimmunoassay accurately detects MB in a concentration of 0-01 mI.U./ml. Plasma MB C.K. in 100 healthy controls averaged 1 mI.U./ml+/-0-6 (S.D.), similar to results in 20 patients with chest pain without infarction. In contrast, in 50 patients with myocardial infarction MB C.K. values averaged 97+/-30 mI.U./ml. When hourly blood-samples from 10 of these patients admitted within an hour of chest pain were analysed by R.I.A., a 100% increase in MB was detectable within four hours of the onset of chest pain, generally before total C.K. exceeded the normal range. Development of an R.I.A. suitable for assay of an isoenzyme in plasma provides a specific and sensitivity assay of MB C.K., facilitating analysis of multiple samples and early detection of myocardial infarction. It may also serve as a prototype for radio-immunoassay of multiple forms of other enzymes of clinical importance.

Acute Disease↗
PubMed1999

Relation between lesion characteristics and risk with percutaneous intervention in the stent and glycoprotein IIb/IIIa era: An analysis of results from 10,907 lesions and proposal for new classification scheme.

BACKGROUND: The currently used American College of Cardiology/American Heart Association lesion classification scheme dates from an era when balloon angioplasty was the only percutaneous treatment available and major complications occurred in approximately 7% of patients. Major advances in treatment options would suggest that this scheme may be outmoded, but the schemes that have been suggested to update lesion classification have not been widely accepted. METHODS AND RESULTS: Four thousand one hundred eighty-one consecutive patients (6,676 lesions) formed a training set and 2,146 patients (4,231 lesions) formed a validation set treated from 1995 to 1997 at a single center used by 3 hospital groups. Twenty-seven pretreatment candidate variables were analyzed with the use of stepwise proportional logistic regression, and 9 (nonchronic total occlusion with TIMI flow 0, degenerated vein graft, vein graft age >10 years, lesion length >/= 10 mm, severe calcium, lesion irregularity, large filling defect, angulated >/= 45 degrees plus calcium, and eccentricity) were independently correlated (P<0.05) with ranked adverse outcome (death, Q-wave or creatine kinase >/= 3x normal myocardial infarction, or emergency coronary artery bypass grafting>>creatine kinase 2 to 3x myocardial infarction>>possibly related to non-Q-wave myocardial infarction>>no complication). A scheme based on these findings and the old American College of Cardiology/American Heart Association scheme were found to have c-statistics in the validation set of 0.672 and 0.620 (P = 0.010 vs old scheme), respectively. CONCLUSIONS: Appreciation of these contemporary risk factors for complications of coronary intervention may assist in patient selection and in risk adjustment for comparison of outcomes between providers.

Adult↗
PubMedDate not supplied

[Various properties of the creatine transport system and the location of creatine kinase in skeletal muscle mitochondria].

Water and creatine contents were studied in rat skeletal muscle mitochondria after their 5 min. incubation in creatine solutions, pH 7.2 or 8.4. The content of water and creatine in mitochondria was found to be higher at pH 8.4, than at pH 72, the creatine content correlated with the water content. Structural creatine analogues, containing aminogroups with pKa greater than or equal to 9.5 or carboxyl groups, inhibited the infusion of creatine into mitochondria more strongly than substances having aminogroups with pKa less than 5. The penetrating form is creatine amphiion; the effect of pH on the permeability is probably due to the activation of the creatine transmitter. Rat skeletal muscle mitochondria contain creatine kinase at both sides of the inner membrane. This conclusion is based on the fact that under conditions, supplying the direct course of the creatine kinase reaction (the incubation medium contains Ca2+ and creatine; pH 7.8), ADP produces the stimulation of mitochondrial respiration up to the oxygen exhausting in a polarographic unit. Similarly, ADP irreversibly stimulates mitochondrial respiration in the presence of 1 mM EDTA, if EDTA and ADP are added after the preincubation of mitochondria in creatine-containing medium and after accumulating small amounts of Ca2+ by mitochondria.

Adenosine Diphosphate↗
PubMed1988

Mitochondrial creatine phosphokinase deficiency in diabetic rat heart.

The role of the mitochondrial end of the phosphocreatine energy shuttle was studied in the streptozotocin diabetic rat heart. Diabetic rats had 45 +/- 5% lower body weight and yielded 46 +/- 6% less mitochondria gm of protein than normals. Diabetic heart mitochondria had 32 +/- 7% lower creatine phosphokinase (CPK) activity and 59 +/- 10% lower oxygen consumption rate than normal heart mitochondria. Creatine (25 mM) did not stimulate oxygen uptake by diabetic heart although control (normal) heart mitochondria were stimulated. Inadequate mitochondrial energy production in the form of phosphocreatine could result in lower energy delivery to the myofibrillar contraction sites and might be an important factor in diabetic cardiomyopathy and weight loss.

Adenine Nucleotides↗
PubMed2003

Diagnostic value of aVL derivation for right ventricular involvement in patients with acute inferior myocardial infarction.

BACKGROUND: Right ventricular (RV) involvement is associated with increased morbidity and mortality in patients with acute inferior myocardial infarction (MI). Although electrocardiography is probably the most useful, simple, and objective tool for the diagnosis of acute MI, there are no well-defined criteria in the standard 12-lead electrocardiogram to properly identify RV involvement in patients with acute inferior MI. Our objective was to evaluate the value of ST-segment depression in lead aVL in diagnosing RV involvement in patients with acute inferior MI. MATERIALS AND METHODS: Sixty-seven patients, hospitalized with acute inferior myocardial infarction, were included in this study. The diagnosis of acute inferior myocardial infarction was based on the clinical history, characteristic enzyme pattern of CK-MB values, and the appearance of ST-segment elevation > or = 1 mm in at least two of the leads (leads II, III, aVF). RV infarction was defined by ST-segment elevation > or = 1mm in lead V4R. ST-segment depression in lead aVL that is more than 1 mm was accepted as a diagnostic criterion for RV involvement in patients with acute inferior MI. RESULTS: Thirty-one patients had >1 mm ST-segment depression and 28 of them had right ventricular infarction according to lead V4R. Thirty-six patients showed < or =1 mm ST-segment depression indicating no right ventricular involvement but four of them also had right ventricular infarction according to V4R. CONCLUSION: More than 1 mm ST-segment depression in lead aVL was found to have high sensitivity (87%), specificity (91%), high positive and negative predictive value (90%, 88%, respectively), and high diagnostic accuracy (89%) in diagnosing RV involvement in patients with acute inferior MI. Therefore, by using a simple 12-lead electrocardiographic sign, ST-segment depression >1 mm in lead aVL, obtained on admission, it is possible to identify RV involvement in patients with acute inferior MI.

Adult↗
PubMed2004

Acute myocardial infarction in a child: possible pathogenic role of patent foramen ovale associated with heritable thrombophilia.

We report an 8-year-old girl who presented with clinical features of an acute myocardial infarction. The angiographic appearance of the coronary arteries was normal. A thrombophilic state caused by a homozygote genotype for the prothrombin G20210A mutation was detected, and a patent foramen ovale (PFO) with right-to-left shunting after Valsalva maneuver was demonstrated by transesophageal contrast echocardiography. No other embolic source was identified. We suggest that paradoxical embolization through a PFO resulted in a myocardial infarction in this young patient with hereditary thrombophilia. We closed the patient's PFO with a 25-mm PFO occluder. She was anticoagulated with warfarin for 6 months. After 6 months, a contrast echocardiogram showed no evidence of residual atrial shunt. There has been no evident recurrent paradoxical embolization.

Child↗
PubMedDate not supplied

[Interaction of various nucleotide-dependent enzymes with bifunctional analogs of ATP, derivatives of polymethylene diamines].

The interaction of bifunctional ATP derivatives, Appp5'[NH-(CH2) n-NH]ppp5'A (n = 0 or 2-8) with tyrosyl-, valyl-, lysyl-, tryptophanyl-tRNA synthetases and creatine kinase was investigated. ATP derivatives don't inhibit the tRNA aminoacylation catalyzed by tyrosyl-tRNA synthetase. These derivatives behave as mixed-type inhibitors with respect to ATP in the case of valyl- and lysyl-tRNA-synthetases. In the case of the other enzymes all analogs of ATP manifest competitive inhibition towards ATP. The affinity of all ATP derivatives to tryptophanyl-tRNA synthetase does not differ significantly (Ki = 0.2 divided by 0.6 mM). The Ki values for these derivatives in the case of creatine kinase are also very similar with the exception of A5'ppp-NH-(CH2)3-NH-ppp5'A. The Ki value for this derivative is one order of magnitude lower than for other ones. The affinity reagents received by periodate oxidation of bifunctional ATP analogs derivatives of di-, tetra- and heptamethylenediamine modify non-identical subunits of creatine kinase with different velocities, but modification of M- and M'-subunits proceeds independently. An analogues derivative of trimethylenediamine interacts simultaneously with two centers of the dimeric form of kinase forming non-equivalent complexes. The covalent attachment of the reagent to one subunit of creatine kinase does not except the complex formation and covalent binding of bifunctional ATP analogs with the other subunit of the dimer, but results in a one order of magnitude decrease in affinity of the ATP derivative to the nonmodified centre of the enzyme. These data permit to evaluate the distance between ATP binding sites of creatine kinase in its dimeric form as 5-6 A approximately. Such a distance between active sites may be the reason for the higher activity of the M- and M'-creatine kinase subunits taken separately as compared to the enzyme dimeric form.

Adenosine Triphosphate↗
PubMed1985

Involvement of hydrogen peroxide and hydroxyl radical in the 'oxygen paradox': reduction of creatine kinase release by catalase, allopurinol or deferoxamine, but not by superoxide dismutase.

The objective of this study was to test the hypothesis that cytotoxic oxygen metabolites participate in lytic cardiac cell damage, detected as creatine kinase release, upon reoxygenation of hypoxic, isolated buffer-perfused hearts (oxygen paradox). Perfusate additives included: superoxide dismutase (30 mg/l); catalase (2 mg/l); deferoxamine (0.5 mM); and allopurinol (1 mM). Creatine kinase release upon reoxygenation was reduced, to levels not significantly different from nonhypoxic controls, by adding either catalase, allopurinol or deferoxamine to the buffer during hypoxia. Reduced creatine kinase leakage was not accompanied by parallel preservation of ventricular function or coronary vascular resistance. Administration of catalase during hypoxia was superior to administering it only during reoxygenation. Treatment with catalase during both hypoxia and reoxygenation provided no more protection than administration only during hypoxia. The data suggest that an important component of hypoxia-induced cardiac cell damage is due primarily to hydrogen peroxide, which may then form hydroxyl radical. Superoxide anion plays an important role as a precursor of these species, but added superoxide dismutase alone did not significantly reduce creatine kinase loss. The data also suggest that damage resulting in creatine kinase release upon reoxygenation occurs during oxygen deprivation, and it is mediated in part by cytotoxic oxygen metabolites.

Allopurinol↗
PubMed1989

Characterization of MB creatine kinase isoform conversion in vitro and in vivo in dogs.

Time-dependent removal of the COOH-terminal lysine residue from each subunit of tissue MM creatine kinase by plasma carboxypeptidase N produces two additional isoforms that are readily separated, thereby permitting sensitive, early detection of acute myocardial infarction. Only two isoforms of MB creatine kinase have been detected in plasma leading to speculation that the COOH-terminal lysine on the B subunit is resistant to hydrolysis. To define the biochemical changes resulting in MB creatine kinase isoform conversion, we incubated highly purified MB creatine kinase from canine myocardium with plasma carboxypeptidase N. Quantitative anion-exchange chromatography of incubation mixtures and serial plasma samples from dogs subjected to coronary occlusion revealed a second, more acidic form evolved with time that was separated from the tissue isoform. Cyanogen bromide digestion of the two isoforms followed by amino acid sequencing of COOH-terminal peptides showed that MB creatine kinase undergoes removal of the COOH-terminal lysine residue from both M and B subunits. An intermediate form lacking lysine on the M subunit was delineated during incubations by the combined use of anion-exchange chromatography and conventional electrophoretic techniques. Thus, sequential cleavage of lysine from subunits of MB creatine kinase produces an intermediate isoform that has not been detected previously because of difficulties separating it from the tissue and fully converted isoforms.

Amino Acid Sequence↗
PubMed1980

Mitochondrial CK (EC 2.7.3.2) in the human heart.

CKm, a mitochondrial form of CK, can be isolated from human cardiac muscle. It occurs in two forms, separable on the basis of the difference in net charge. Both molecules have a dimeric structure and consist of two identical subunits. Upon incubation in a human serum, the CK isozyme with the faster cathodal mobility is rapidly converted into the slower form, which has an isoelectric point of 6.94. This makes it impossible to separate this slow CKM form from CK MM (isoelectric point: 6.86) by means of any method that separates on a basis of differences in net charge. Furthermore the two molecules have an almost identical molecular weight. The only difference between the two molecules we have been able to detect is the different behaviour against anti-M antibodies.

Creatine Kinase↗
PubMed1989

Hemin enhances differentiation and maturation of cultured regenerated skeletal myotubes.

Satellite cells, isolated from marcaine-damaged rat skeletal muscle, differentiate in culture to form contracting, cross-striated myotubes. Addition of 20 microM hemin (ferriprotoporphyrin IX chloride) to the culture medium resulted in increases in the number, size, and alignment of myotubes; in the number of myotubes that exhibited cross-striations; and in the strength and frequency of myotube contractions. Hemin increased satellite cell fusion by 27%, but decreased cell proliferative rate by 30%. Hemin increased the specific activity of creatine kinase (CK), a sensitive indicator of muscle differentiation, by 157%. Separation of CK isoenzymes by agarose gel electrophoresis showed that hemin increased only the muscle-specific CK isoenzymes (MM-CK and MB-CK). Thus, hemin seems to duplicate some of the effects of innervation on cultured myotubes by increasing contraction frequency and strength, appearance of cross-striations, and muscle-specific isoenzymes. In contrast, 3-amino-1,2,4-triazole, an inhibitor of heme biosynthesis, decreased the number of cross-striated myotubes, the strength and frequency of myotube contractions, and CK activity. These inhibitory effects were reversed by hemin. Collectively, these results demonstrate a physiologically significant role for heme in myotube maturation.

Animals↗
PubMed2001

Early biochemical indicators of hypoxic-ischemic encephalopathy after birth asphyxia.

Hypoxic-ischemic encephalopathy (HIE) after perinatal asphyxia is a condition in which serum concentrations of brain-specific biochemical markers may be elevated. Neuroprotective interventions in asphyxiated newborns require early indicators of brain damage to initiate therapy. We examined brain-specific creatine kinase (CK-BB), protein S-100, and neuron-specific enolase in cord blood and 2, 6, 12, and 24 h after birth in 29 asphyxiated and 20 control infants. At 2 h after birth, median (quartiles) serum CK-BB concentration was 10.0 U/L (6.0-13.0 U/L) in control infants, 16.0 U/L (13.0-23.5 U/L) in infants with no or mild HIE, and 46.5 U/L (21.4-83.0 U/L) in infants with moderate or severe HIE. Serum protein S-100 was 1.6 microg/L (1.4-2.5 microg/L) in control infants, 2.9 microg/L (1.8-4.7 microg/L) in asphyxiated infants with no or mild HIE, and 17.0 microg/L (3.2-34.1 microg/L) in infants with moderate or severe HIE 2 h after birth. No significant difference was detectable in serum neuron-specific enolase between infants with no or mild and moderate or severe HIE 2 and 6 h after birth. A combination of serum protein S-100 (cutoff value, 8.5 microg/L) and CK-BB (cutoff value, 18.8 U/L) 2 h after birth had the highest predictive value (83%) and specificity (95%) of predicting moderate and severe HIE. Cord blood pH (cutoff value, <6.9) and cord blood base deficit (cutoff value, >17 mM) increase the predictive values of protein S-100 and CK-BB. We conclude that elevated serum concentrations of protein S-100 and CK-BB reliably indicate moderate and severe HIE as early as 2 h after birth.

Asphyxia↗
PubMed1988

Quantitative analysis for isoforms of creatine kinase MM in plasma by chromatofocusing, with on-line monitoring of enzyme activity.

Changes in the proportions of individual isoforms of the MM isoenzyme of creatine kinase (CK; EC 2.7.3.2) in plasma promptly reflect both myocardial infarction and coronary recanalization. However, quantitative methods developed thus far are too slow or cumbersome for routine use in making clinical decisions. We report a convenient, quantitative chromatofocusing assay with on-line fluorometric detection of isoform activity in the column eluent that provides results within 40 min from the time of sample application. Sample eluted from a microbore chromatofocusing column (1.8-mL bed volume) is split between a reaction stream, into which CK reagents are added, and a reference stream. After incubation at 37 degrees C, NADPH formed by reaction of isoforms with CK reagent is detected at 340 nm. The system can detect activity of individual isoforms in plasma samples having total CK activity greater than or equal to 21 U/L (30 degrees C). Results correlated closely with those obtained by previously validated, but slow, chromatofocusing (r = 0.98, n = 30) and protein immunoblotting (r = 0.90, n = 20) procedures.

Animals↗
PubMed2001

Varicella myocarditis in an adult.

A 24 year old male with varicella myocarditis was admitted with chest pain and fever up to 39 degrees C. The ECG showed J point and ST elevation in leads V2-V4, and inverted T waves in leads V5 and V6. Creatine kinase (CK) was raised to 435 U/l (CK-MB 36 U/l), troponin I was 63.4 microgram/l, and lactate dehydrogenase was 359 U/l, suggesting cardiac involvement of varicella infection. The left ventricle was dilated (58 mm) and left ventricular ejection fraction was globally reduced (ejection fraction 45%). Myocarditis was confirmed by endomyocardial biopsy. The patient was treated with specific varicella hyperimmunoglobulins, aciclovir, and a non-steroidal anti-inflammatory drug. During two months follow up the patient recovered completely. This case report is a reminder that a varicella infection can cause myocarditis in adults. Early diagnosis and appropriate treatment of this rare form of myocarditis may lead to complete recovery.

Adult↗