Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Bio 14.6 cardiomyopathic Syrian hamster is an animal model of human idiopathic cardiomyopathy. The pathogenesis of the disease in this animal has not yet been clearly elucidated. It is well known that alpha- and beta-adrenergic receptors are increased in the myocardium of this animal, but that isoprenaline does not produce an augmented response. We examined the activity of cardiac stimulatory GTP-binding protein (Gs), which couple with beta-adrenergic receptors to stimulate adenylate cyclase, in Bio 14.6 cardiomyopathic hamsters at 90 and 160 days of age. The cardiac norepinephrine concentration was significantly increased in Bio 14.6 hamsters compared with control hamsters (F1B) at 90 days of age (1,739 +/- 120 vs 1,470 +/- 161 ng/g wet tissue weight, p less than 0.05). Cardiac forskolin-stimulated adenylate cyclase activities at 90 and 160 days of age were lower in the cardiomyopathic hamsters than in the F1B controls (90 days old: 98 +/- 24 vs 122 +/- 29 pmol/min/mg protein, p less than 0.05; 160 days old: 74 +/- 13 vs 124 +/- 28 pmol/min/mg protein, p less than 0.01). Cardiac Gs activities at 90 and 160 days of age were significantly lower in Bio 14.6 hamsters than those in F1B hamsters (90 days old: 204 +/- 42 vs 259 +/- 49 pmol/min/mg protein, p less than 0.05; 160 days old: 156 +/- 39 vs 211 +/- 60 pmol/min/mg protein, p less than 0.05). We thus demonstrated functional defects in cardiac Gs protein and adenylate cyclase activity in the Bio 14.6 cardiomyopathic hamsters at 90 to 160 days of age (the hypertrophic stage of cardiomyopathy).(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1992 Mar 04
PMID:Stimulatory guanine nucleotide-binding protein and adenylate cyclase activities in Bio 14.6 cardiomyopathic hamsters at the hypertrophic stage. 131 29

Na+,K(+)-ATPase is a major determinant of myocyte homeostasis and excitation-contraction. Cardiac glycosides such as digitalis and ouabain increase the inotropic state of the heart through the inhibition of Na+,K(+)-ATPase. While cardiac glycosides are commonly used in the setting of congestive heart failure, optimal therapy would depend upon an intact Na+,K(+)-ATPase system. Changes in Na+,K(+)-ATPase activity and glycoside receptor density with the development of cardiomyopathy have not been well defined. Accordingly, left ventricular (LV) function and Na+,K(+)-ATPase activity and glycoside binding were examined in 7 pigs with dilated cardiomyopathy and in 7 controls. Dilated cardiomyopathy was produced by pacing induced supraventricular tachycardia (SVT) for 3 weeks at 240 bpm. Left ventricular function was examined by simultaneous echocardiography and catheterization. Left ventricular fractional shortening significantly decreased with SVT (34 +/- 2 vs. 10 +/- 2%, P less than 0.05) and LV diastolic dimension and pressure significantly increased (3.8 +/- 0.3 vs. 5.1 +/- 0.4 cm, and 8 +/- 2 vs. 27 +/- 2 mmHg, respectively, P less than 0.05) as compared to controls. Na+,K(+)-ATPase activity was assayed as potassium dependent p-nitrophenol-phosphatase activity. Glycoside receptor density (Bmax) and affinity (KD) was determined using [3H]-ouabain binding assays. Na+,K(+)-ATPase activity, Bmax, and KD all significantly fell from control values with SVT induced cardiomyopathy (0.64 +/- 0.06 vs. 0.45 +/- 0.12 micrograms pNP/mg/h, 5.5 +/- 0.4 vs. 1.9 +/- 0.4 pmol/mg, and 15 +/- 3 vs. 9 +/- 3 nM, respectively, P less than 0.05). The distribution of Na+,K(+)-ATPase in LV sections taken from control and SVT hearts were examined using immunohistochemical techniques. A patchy distribution of Na+,K(+)-ATPase along the sarcolemma in SVT sections was observed as opposed to a more uniform distribution in control myocytes. There was no observable change in the relative content and distribution of the Na+,K(+)-ATPase isoforms alpha 2 and alpha 3 in the SVT sections as compared to controls. In an additional set of experiments, changes in LV as well as isolated myocyte responsiveness to ouabain were examined. Left ventricular fractional shortening and peak dP/dt were measured following administration of 20-60 micrograms/Kg of ouabain in control (n = 3) and SVT (n = 3) pigs. In the control group, 40 micrograms/Kg caused a 25% in LV fractional shortening and a 60% increase in peak dP/dt from baseline. Cumulative doses of 60 micrograms/Kg in the control pigs resulted in over a 75% increase in peak dP/dt from baseline values.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1992 Mar
PMID:Myocardial Na+,K(+)-ATPase in tachycardia induced cardiomyopathy. 132 Jul 3

In a comparison using age-matched Wistar-Kyoto rats (WKY), 16-week-old male spontaneously hypertensive rat (SHR) hearts were examined histologically and biochemically on the first and fourth day after administration of 20 mg/kg doxorubicin in order to examine whether membrane abnormalities in hypertrophied SHR myocardium are caused by lipid peroxidation. Morphological examination of the SHR revealed focal myocytolysis on the first day and severe cardiomyopathy involving diffuse myocytolysis and vacuolar degeneration in the left ventricle on the fourth day. The activity of a membrane-related enzyme, Na+/K(+)-ATPase, was already lower in control SHR than that of control WKY and was lower in both SHR and WKY than in the respective saline groups on the first day after administration, whereas the enzyme activity in the doxorubicin-treated SHR was not significantly different from that of the treated WKY. A thiobarbituric acid-reactant substance, a lipid peroxidation marker, was significantly higher in treated SHR than it was in the treated WKY on the first day. Furthermore, in comparison with WKY, alpha-tocopherol in the left ventricle in SHR was significantly lower on the fourth day after administration. These results show that a proneness to lipid peroxidation in the membrane system is closely associated with severity of doxorubicin-induced cardiomyopathy in SHR and suggests that membrane lipid peroxidation may cause a higher degree of vulnerability in hypertrophied SHR myocardium.
Exp Mol Pathol 1992 Aug
PMID:Lipid peroxidation and myocardial vulnerability in hypertrophied SHR myocardium. 132 61

Using saponin skinned fibers, we investigated whether decreased myofilament calcium responsiveness and contractile activation may in part contribute to heart failure in an animal model of idiopathic spontaneous cardiomyopathy (SCM). We addressed the question as to whether there are adaptive changes at the level of the thin myofilaments in turkey poults with SCM. The calcium concentration ([Ca2+]) required for 50% activation ([Ca2+]50%) was 0.80 +/- 0.12 microM (n = 12) vs. 0.76 +/- 0.08 microM (n = 12) and the Hill coefficient was 1.98 +/- 0.20 (n = 12) vs. 2.14 +/- 0.38 (n = 12) for control and SCM muscles respectively. Maximal Ca(2+)-activated force was not different between control fibers and fibers from failing hearts (3.83 +/- 0.88 g/mm2 vs. 3.65 +/- 0.39 g/mm2). These data indicate there are no differences in calcium-activation between fibers from control and failing myocardium. The effects of caffeine, an agent that increases myofilament Ca2+ sensitivity, were also studied. Addition of 10 mM caffeine resulted in a 0.06 pCa unit leftward shift of the force-pCa relationship in control hearts and 0.14 pCa units in SCM hearts. Caffeine (30 mM) increased force by 26 +/- 2.1% (n = 7) in control fibers and 44.5 +/- 8.7% (n = 8) in myopathic fibers at a pCa of 6.0. The increased responsiveness of muscles from failing hearts to caffeine indicates adaptive changes at the level of the thin myofilaments. Addition of dibutyryl-3',5'-cyclic-Adenosine Monophosphate (D-cAMP) resulted in a 0.21 pCa rightward shift on the calcium axis to higher intracellular calcium concentrations in control myocardium and 0.38 pCa units in SCM failing myocardium. The muscles were also sinusoidally oscillated at frequencies ranging between 0.01 and 100 Hz. In this analysis the frequency at which dynamic stiffness is minimum is taken as a measure of cross-bridge cycling rate. In control muscles, the frequency of minimum stiffness (fmin) was 1.20 +/- 0.11 (n = 4) whereas it was 0.71 +/- 0.08 Hz (n = 4) in myopathic muscles. The addition of 10 microM D-cAMP shifted fmin from 1.20 +/- 0.11 Hz to 1.68 +/- 0.09 Hz (delta = 0.48 +/- 0.06) in control fibers whereas in SCM fibers it caused greater shift of fmin from 0.71 +/- 0.08 Hz to 1.73 +/- 0.08 Hz (delta = 1.02 +/- 0.07). This differential effect of D-cAMP indicates adaptive changes at the level of the myofilaments.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1992 Dec
PMID:Calcium-activated force in a turkey model of spontaneous dilated cardiomyopathy: adaptive changes in thin myofilament Ca2+ regulation with resultant implications on contractile performance. 133 13

Malnutrition has been associated with changes in cardiac metabolism and performance. We have previously reported a diabetic-type cardiomyopathy associated with chronic food restriction and weight loss. Because the creatine-phosphocreatine-creatine kinase system is important in the contractile process, we studied the components of this system in rats fed a food-restricted diet (33% of control animal intake). After 4 weeks of food restriction, total creatine kinase (CK) activities were reduced by 28% in ventricles and by 38% in atria. The CK isoenzymes in the heart were not equally affected. The BB isoenzyme was decreased by 77% and 78%, the MB isoenzyme by 45% and 43%, the MM isoenzyme by 22% and 19% and CKmito by 16% and 15% in ventricles and atria, respectively. In contrast, brain CK activity which is predominantly the BB isoenzyme, was slightly higher in the food-restricted than in control rats. Further studies on ventricular tissue from food-restricted rats revealed a 27% decline in myofibrillar CR activity and a 58% decline in myofibrillar ATPase activity. Phosphocreatine and creatine concentrations were not changed by food restriction, however, ATP was decreased by 23% in ventricles from rats on the restricted diet. Cardiac mitochondrial oxidative phosphorylation was also impaired. State 3 respiration with alpha-ketoglutarate was reduced 20% in the food-restricted heart. These changes are compared to those which we previously observed in the diabetic rat heart and the significance of these findings is discussed.
J Mol Cell Cardiol 1992 Aug
PMID:Effect of food restriction on the phosphocreatine energy shuttle components in rat heart. 143 12

The activity of the phospholipid base exchange enzyme specific for ethanolamine has been measured in cardiac sarcolemmal membrane preparations from Syrian golden and UM-X7.1 cardiomyopathic hamsters. In Syrian golden hamsters, the Km of the enzyme for ethanolamine does not change with age, whereas it almost doubles in membranes from cardiomyopathic animals, from the 30th to the 150th day of age. During the same period, the membrane cholesterol content increases by 68% in cardiomyopathic hamsters, whereas it does not change significantly in the Syrian golden hamster strain. As a consequence, in the adult animal, the cholesterol to phospholipid ratio and the viscosity of sarcolemmal membranes are higher in UM-X7.1 strain than in Syrian golden hamsters. A cause-consequence relationship between the enzymatic changes and the compositional modifications in the sarcolemma occurring in UM-X7.1 hamsters during the development of cardiomyopathy is proposed.
Mol Cell Biochem 1992 Oct 21
PMID:Kinetic changes of ethanolamine base exchange activity and increase of viscosity in sarcolemmal membranes of hamster heart during development of cardiomyopathy. 148 Jan 58

The functional integrity of the beta-adrenergic stimulatory pathway in a rabbit model of heart failure induced by long-term adriamycin treatment was investigated. Adriamycin-induced cardiomyopathy was produced in 46 rabbits by injecting 0.75 mg/kg of adriamycin, three times per week, for a period of 11 weeks. Biochemical studies performed on isolated membrane preparations revealed a 40 and 55% decrease in basal adenylyl cyclase activity in the left and right ventricles of the adriamycin treated rabbits, respectively. Furthermore, the Vmax of forskolin stimulation was significantly lower in both ventricles with no change in Kact. The Vmax of 5'-guanylylimidodiphosphate stimulation of the stimulatory guanylyl nucleotide binding protein Gs and beta-adrenergic receptor stimulation by isoproterenol were also significantly decreased (42%) in both ventricles of the adriamycin-treated rabbits with no change in Kact. Despite the decrease in receptor-mediated cyclic AMP production, no decrease in beta-adrenergic receptor population was found. Mechanical studies on the isolated right ventricular papillary muscle revealed a decrease in baseline total tension (3.1 +/- 0.4 g/mm2 to 1.8 +/- 0.2 g/mm2) and dT/dt (15.1 +/- 1.6 g/mm2 s to 7.9 +/- 0.8 g/mm2 s) in the adriamycin-treated rabbits. Furthermore, tension generation and dT/dt response to increasing concentrations of forskolin or isoproterenol were both significantly lower in the adriamycin-treated rabbits as compared to normal. We suggest that a decrease in the activity of the adenylyl cyclase component of the beta-adrenergic stimulatory pathway is largely responsible for the decrease in cyclic AMP generation in the adriamycin-treated rabbits. This defect may play an important role in the decrease of contractility in this model of heart failure.
J Mol Cell Cardiol 1991 Mar
PMID:Adriamycin-induced changes to the myocardial beta-adrenergic system in the rabbit. 165 46

Cardiovascular disease represents the major cause of morbidity and mortality in noninsulin-dependent diabetic patients. While it was once thought that atherosclerotic vascular disease was responsible for all of these adverse effects, recent studies support the notion that one of the major adverse complications of diabetes is the development of a diabetic cardiomyopathy characterized by defects in both diastolic and systolic function. Contributing to the development of the cardiomyopathy is a shift in myosin isozyme content in favor of the least active V3 form. Also defective in the noninsulin-dependent diabetic heart is regulation of calcium homeostasis. While transport of calcium by the sarcolemmal and sarcoplasmic reticular calcium pumps are minimally affected by noninsulin-dependent diabetes, significant impairment occurs in sarcolemmal Na(+)-Ca2+ exchanger activity. This defect limits the ability of of the diabetic heart to extrude calcium, contributing to an elevation in [Ca2+]i. Also promoting the accumulation of calcium by the diabetic cell is a decrease in Na+, K+ ATPase activity, which is known to increase [Ca2+]i secondary to a rise in [Na+]i. In addition, calcium influx via the calcium channel is stimulated. Although the molecular mechanisms underlying these defects are presently unknown, the possibility that they may be related to aberrations in glucose or lipid metabolism are considered. The evidence suggests that classical theories of glucose toxicity, such as excessive polyol production or glycosylation, appear to be insignificant factors in heart. Also insignificant are defects in lipid metabolism leading to accumulation of toxic lipid amphiphiles or triacylglycerol. Rather, the major defects involve membrane changes, such as phosphatidylethanolamine N-methylation and protein phosphorylation, which can be attributed to the state of insulin resistance.
Mol Cell Biochem 1991 Sep 18
PMID:Cardiomyopathy associated with noninsulin-dependent diabetes. 166 89

Morphologic changes in Doxorubicin (DXR)-induced cardiomyopathy are characterized by marked dilatation of the sarcoplasmic reticulum (SR). DXR was administered to New Zealand White rabbits for 5 or 8 weeks and the three-dimensional structure of the sarcotubular system in cardiac muscle cells from each rabbit was examined under a field-emission type scanning electron microscope (SEM) after removal of cytoplasmic matrices by the osmium-DMSO-osmium procedure. Five weeks after the initial injection of DXR, partial dilatation of the SR and damaged mitochondria with lysis of cristae were observed three-dimensionally. After 8 weeks, the three-dimensional structure of the SR showed extensive spherical ballooning which could be seen clearly in bold relief. Thus, we could directly visualize structural alterations of the sarcotubular system in DXR-induced cardiomyopathy using the SEM.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Ultrastructural alterations of the myocardium induced by doxorubicin. A scanning electron microscopic study. 167 75

Doxurubicin is an effective and widely used chemotherapeutic agent. However, use of this drug is often limited by its cardiotoxic side effects. We have observed that an early event accompanying doxorubicin cardiomyopathy is a selective decrease in levels of muscle gene transcripts in cardiac tissue (Ito et al., Proc. Natl. Acad. Sci. USA 87: 4275-4279). Since this decrease precedes ultrastructural evidence of cardiac damage, measurements of muscle transcripts might assist in the clinical evaluation of doxorubicin cardiotoxicity. We have therefore assessed the utility of the polymerase chain reaction in the measurement of mRNA in control and doxorubicin-treated animals. These measurements were performed on small tissue samples that simulate endomyocardial biopsies. We measured cardiac alpha-actin transcripts as a fraction of ferritin heavy chain transcripts using the method described by Chelly et al. (Nature 333: 858-860, 1988). 0.5 micrograms of total RNA, an amount equivalent to that obtainable from a typical endomyocardial biopsy, was efficiently co-amplified with cardiac alpha-actin and ferritin heavy chain specific primers. The cardiac alpha-actin/ferritin heavy chain ratio calculated from the PCR results correlated well (R = 0.981) with results obtained using Northern blot analysis of 10 micrograms RNA. The correlation was maintained over a wide range of cardiac alpha-actin transcript abundance. These results show that mRNA from cardiac tissue can be estimated by the polymerase chain reaction, even from a small, endomyocardial biopsy-sized sample.
J Mol Cell Cardiol 1991 Oct
PMID:Evaluation of mRNA levels by the polymerase chain reaction in small cardiac tissue samples. 174 3


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