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)

Studies of hemodynamics and intrinsic left ventricular myocardial function are carried out to investigate the transition from stable hypertrophy to cardiac decompensation in the aging (18-24 months) spontaneously hypertensive rat (SHR). Echocardiographic data in awake animals demonstrate increased end-diastolic and end-systolic volumes and depressed ejection fractions in left ventricles from SHR with failure (SHR-F) as compared to age matched hypertensive (SHR-NF) and non-hypertensive control animals (WKY). Cardiac catheterization data in anesthetized animals demonstrate depression of both systolic pressure and +dP/dt, and elevated end-diastolic pressure in the SHR-F relative to the two control groups. Since loading conditions and altered demand states may contribute to altered ventricular function, studies of isolated perfused hearts were carried out which demonstrate impaired systolic stress development in the SHR-F group under conditions in which loading conditions are controlled; in addition, it is observed that increasing perfusion pressure by 30 mm Hg has little effect on function. Depression of systolic function and increases in passive stiffness of isolated muscle preparations from the SHR-F indicate impairment of systolic and diastolic function at the tissue level. While all of the preparations studied have potential shortcomings, an integration of findings from these complementary approaches supports the conclusion that heart failure develops in the aging SHR. Furthermore, these data suggest that impaired function is due to changes in the intrinsic properties of the myocardium and that the connective tissue response may play an important role. These studies, in conjunction with the findings of others who have studied the aging SHR, provide support for the use of the aging SHR as a model of the transition from compensated hypertrophy to failure.
J Mol Cell Cardiol 1995 Jan
PMID:The spontaneously hypertensive rat as a model of the transition from compensated left ventricular hypertrophy to failure. 776 Mar 60

The three-dimensional structures of native partridge egg-white lysozyme (PEWL) and PEWL complexed with tri-N-acetylchitotriose inhibitor have been determined crystallographically and refined at 1.9 A resolution. Crystals of native and complexed protein are isomorphous and have space group and cell dimensions that are identical to those of hen egg-white lysozyme (HEWL) under similar crystallization conditions. Full occupancy of the trisaccharide in the inhibitor complex has allowed definitive modeling and refinement of all three sugar residues, located at subsites A, B, and C in the PEWL active site. A comparison has been made with HEWL/inhibitor complexes in which coordinates were either not refined (Blake CCF, et al., 1967, Proc R Soc B 167:378-388) or were refined at partial occupancy (Cheetham JC, Artymiuk PJ, Phillips DC, 1992, J Mol Biol 224:613-628). Although the loop comprising residues 70-75 is located on the surface of the protein and not near the active site, it appears to be affected indirectly by trisaccharide binding such that the loop shifts toward the active site and becomes relatively immobilized. The source of this loop movement appears to be the anchoring of Trp62, located in the active site cleft, as it forms a hydrogen bond with O6 of the N-acetylglucosamine at site C. Good electron density for the trisaccharide in the PEWL complex structure shows that Asp 101 is involved in hydrogen bonding interactions with the terminal sugar residue.
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PMID:Structures of partridge egg-white lysozyme with and without tri-N-acetylchitotriose inhibitor at 1.9 A resolution. 779 28

The ets-1 protein has been primarily studied as a sequence-specific transcriptional regulator that is predominately expressed in lymphoid cells. In this report, we show that ets-1 is also expressed in astrocytes and astrocytoma cells and is regulated during both signal transduction and differentiation. Both isoforms of ets-1, p51 and p42, were found in astrocytes and astrocytoma cells, but whereas expression of p51 was strong, p42, the alternate splice product previously shown to lack the phosphorylation domain, was difficult to detect and was present at a level 10- to 40-fold lower than that of p51. This differed by roughly an order of magnitude from the ratio generally observable in T cells and thymocytes. In two astrocytoma lines of human origin, CCF and 1321N1, ets-1 phosphorylation was stimulated by bradykinin and carbachol, respectively. Glutamate, norepinephrine, and bradykinin elicited phosphorylation of p51 in cultures of primary rat type 1 astrocytes. ets-1 phosphorylation was dramatically blocked by KT5926, an inhibitor of myosin light-chain kinase, suggesting that this kinase may be involved in phosphorylation of ets-1 in vivo. Investigations of retinoic acid-induced differentiation in P19 cells provided further support for a strong correlation of ets-1 with the pathway for astrocyte differentiation.
Mol Cell Biol 1995 Feb
PMID:ets-1 in astrocytes: expression and transmitter-evoked phosphorylation. 782 57

In order to explain the attenuated sympathetic support during the development of heart failure, the status of beta-adrenergic mechanisms in the failing myocardium was assessed by employing cardiomyopathic hamsters (155-170 days old) at moderate degree of congestive heart failure. The norepinephrine turnover rate was increased but the norepinephrine content was decreased in cardiomyopathic hearts. The number and the affinity of beta receptors in the sarcolemmal preparations were not changed in these hearts at moderate stage of congestive heart failure. While the basal adenylyl cyclase activity was not altered in sarcolemma, the stimulation of enzyme activity by NaF, forskolin, Gpp(NH)p or epinephrine was depressed in hearts from these cardiomyopathic hamsters. Since G-proteins are involved in modifying the adenylyl cyclase activity, the functional and bioactivities as well as contents of both Gs and Gi proteins were determined in the cardiomyopathic heart sarcolemma. The functional stimulation of adenylyl cyclase by cholera toxin, which activates Gs proteins, was markedly depressed whereas that by Pertussis toxin, which inhibits Gi proteins, was markedly augmented in cardiomyopathic hearts. The cholera toxin and pertussis toxin catalyzed ADP-ribosylation was increased by 37 and 126%, respectively; this indicated increased bioactivities of both Gs and Gi proteins in experimental preparations. The immunoblot analysis suggested 74 and 124% increase in Gs and Gi contents in failing hearts, respectively. These results suggest that depressed adenylyl cyclase activation in cardiomyopathic hamsters may not only be due to increased content and bioactivity of Gi proteins but the functional uncoupling of Gs proteins from the adenylyl cyclase enzyme may also be involved at this stage of heart failure.
Mol Cell Biochem 1994 Nov 23
PMID:Alterations in G-proteins in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters. 789 87

In this study we used 2.5% myocardial homogenates to study sarcoplasmic reticulum (SR) activity of the Ca2+ pump and Ca2+ release channel (CRC) from dogs with congestive heart failure produced by either rapid ventricular pacing or idiopathic dilated cardiomyopathy. We used the fluorescent indicator dye and ratiometric spectrofluorometry to monitor Ca2+ uptake while the CRC was open and closed with ryanodine. We confirmed and extended conclusions derived from previous studies of the same dogs using isolated SR. Compared to controls, activities of dogs with either form of CHF were decreased by 36% for the Ca2+ pump (33.7 +/- 7.3 and 21.6 +/- 4.2 nM/s), 78% for the CRC (10.0 +/- 2.8 and 1.4 +/- 1.2 nM/s), 53% for total Ca2+-cycling (53.1 +/- 8.5 and 24.8 +/- 4.4 nM/s), and 17% for net Ca2+ uptake (23.7 +/- 4.0 and 19.6 +/- 4.0 nM/s). In the absence of SR and mitochondrial activity, ionized Ca2+ concentration in myocardial homogenates were 70% abnormally increased in dogs with CHF, probably due to decreased concentration of Ca2+-binding proteins. Comparison of homogenate and isolated SR activities indicated lower-than-normal membrane yields for dogs with CHF. This fractionation artefact previously resulted in up to 50% overestimation of the degree of downregulation of Ca2+-cycling activities in CHF. The CRC activity was found to be decreased due to decreased activity of the Ca2+-ATPase, decreased CRC content, and inhibition. Decreased CRC energy. Maintenance of net Ca2+-pump activity is expected to maintain the amplitude of the myocardial ionized Ca2+ transient whereas downregulation of the CRC and pump are predicted to reduce the total amount of Ca2+ cycled and slow the rise and fall of the Ca2+ transient.
J Mol Cell Cardiol 1994 Feb
PMID:Compensatory asymmetry in down-regulation and inhibition of the myocardial Ca2+ cycle in congestive heart failure produced in dogs by idiopathic dilated cardiomyopathy and rapid ventricular pacing. 800 78

Atrial natriuretic peptide (ANP) is a natriuretic, diuretic and vasodilatory peptide normally synthesized and secreted by the atria of the adult mammalian heart. Synthesis of ANP in the ventricle has also been demonstrated in the fetus and neonate. In the adult, ventricular ANP is expressed under pathological conditions such as hypertension and congestive heart failure. The purpose of the present study was to analyse the spatial and temporal development of ANP expression in the right ventricle of the rat heart during the onset, establishment, and recovery from hypoxia-induced pulmonary hypertension and right ventricular hypertrophy (RVH). Significant RVH and immunoreactive ANP (ir-ANP) were detected in the right ventricles of hypoxic rats after only 3 days of exposure and continued to increase with the duration of hypoxia through 21 days. The presence of ir-ANP became apparent in the left ventricle as well as the right after 14 days of hypoxic exposure. Twenty-one days of normoxia following 21 days of hypoxia reduced RVH and ir-ANP to the levels seen at 3 days. Light microscopic immunohistochemistry demonstrated initial focal concentrations of ir-ANP in cardiomyocytes near the junction of the right ventricular free wall and the septum, as well as surrounding isolated blood vessels in the right ventricular wall, after 3 days of exposure. With increasing duration of hypoxic exposure, these immunoreactive areas enlarged to encompass the entire right ventricular wall and right half of the septum by 14 days. While many right ventricular cardiomyocytes were intensely stained at the light level, electron microscopic immunocytochemistry revealed only a sparse number of ANP-positive secretory granules. In immunohistochemical studies with an anti-clathrin antibody, there was a homogeneous staining pattern for clathrin in cardiomyocytes from the hypertrophied right ventricles. This pattern was not typical of the staining observed in other secretory cells which typically exhibit a perinuclear localization of clathrin. The alterations in ultrastructural immunocytochemistry for ANP suggest that ventricular ANP synthesis differs from atrial synthesis of this peptide. The differences in clathrin staining indicate that its expression may also be related to the hypertrophic adaptation of ventricular cardiomyocytes. Our results suggest that ventricular ANP expression in the adult rat is a dynamic event which is regulated by stress in the ventricular wall. The initial sites of ventricular ANP expression may represent zones of maximum tension in the ventricular wall following increased workload. To our knowledge this is the first study to demonstrate topographical changes in ventricular ANP expression in response to the development and reversal of cardiac hypertrophy.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1994 Jun
PMID:Developmental pattern of ventricular atrial natriuretic peptide (ANP) expression in chronically hypoxic rats as an indicator of the hypertrophic process. 808 55

The rat model of myocardial infarction is characterized by progressive cardiac hypertrophy and failure. Rats with infarcts greater than 30% of the left ventricle exhibited early and moderate stages of heart failure 4 and 8 weeks after the occlusion of the left coronary artery, respectively. As heart failure is usually associated with remodeling of the extracellular matrix, a histological and biochemical study of cardiac collagenous proteins was carried out using failing hearts. Total collagen content in the right ventricle increased at 2, 4, and 8 weeks following occlusion of the left coronary artery whereas such a change in viable left ventricle was seen after 4 and 8 weeks. Total cardiac hydroxyproline concentration was increased in both right and left ventricular samples from the infarcted animals when compared to those of control; this increase was due to elevation of pepsin-insoluble collagen fraction. The myocardial noncollagenous/collagenous protein ratio was decreased in experimental right and left ventricular samples when compared to control samples. These findings suggest that an increase in cross-linking of cardiac collagen as well as disparate synthesis of collagenous and noncollagenous proteins occurs in this model of congestive heart failure.
Mol Cell Biochem 1993 Dec 22
PMID:Alteration of collagenous protein profile in congestive heart failure secondary to myocardial infarction. 817 34

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopril-treated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5-75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.
Mol Cell Biochem 1993 Dec 22
PMID:Beneficial effect of ACE inhibitor in congestive heart failure. 817 36

The cardiac interstitium is populated by nonmyocyte cell types including transcriptionally active cardiac fibroblasts and endothelial cells. Since these cells are the source of many components of the cardiac extracellular matrix, and because changes in cardiac extracellular matrix are suspected of contributing to the genesis of cardiovascular complications in disease states such as diabetes, hypertension, cardiac hypertrophy and congestive heart failure, interest in the mechanisms of activation of fibroblasts and endothelial cells has led to progress in understanding these processes. Recent work provides evidence for the role of the renin-angiotensin-aldosterone system in the pathogenesis of abnormal deposition of extracellular matrix in the cardiac interstitium during the development of inappropriate cardiac hypertrophy and failure. The cardiac extracellular matrix is also known to change in response to altered cardiac performance associated with post-natal aging, and in response to environmental stimuli including intermittent hypoxia and abnormal nutrition. It is becoming clear that the extracellular matrix mainly consists of molecules of collagen types I and III; they form fibrils and provide most of the connective material for typing together myocytes and other structures in the myocardium and thus is involved in the transmission of developed mechanical force. The data available in the literature support the view that the extracellular matrix is a dynamic entity and alterations in this structure result in the development of heart dysfunction.
Mol Cell Biochem 1993 Dec 22
PMID:Role of extracellular matrix proteins in heart function. 817 33

This study examined the potential role of ET-1 and the contribution of protein kinase C (PKC) in the desensitization of the ET-1 transmembrane signaling pathway in the left circumflex coronary artery (CCA) of a dog model of congestive heart failure (CHF). In the CCA of the rapid ventricular pacing-overdrive dog model of CHF, elevated plasma endothelin levels were associated with a decrease in the basal accumulation of inositol phosphates and ET-1 mediated activation of phosphatidylinositol (PI) turnover (P < 0.05). To assess whether elevated plasma ET-1 levels may have contributed to the diminished ET-1 responsiveness in the heart failure dogs, ET-1 generation of inositol phosphates was measured following a one hour pretreatment of normal coronary artery rings with 0.1 nM ET-1. As compared to non-treated rings, ET-1 pretreatment resulted in a 33% decrease of ET-1 (10 nM) production of inositol phosphates. To evaluate the role of PKC in this process, normal coronary rings pretreated for a period of one hour with the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), resulted in a similar attenuation (36%) of ET-1 production of inositol phosphates. In the presence of the protein kinase C inhibitor staurosporine, both the agonist and phorbol ester induced decreases in ET-1 mediated PI turnover were reversed. Staurosporine even potentiated (75%) ET-1 induced PI turnover despite ET-1 and PMA pretreatments. These results suggest that agonist-induced desensitization of ET-1 mediated PI turnover can occur and is at least one of the possible mechanisms contributing to the desensitization of the ET-1 transmembrane signaling pathway in the pacing-overdrive model of heart failure in the dog.
J Mol Cell Cardiol 1993 Aug
PMID:Regulation of the endothelin-1 transmembrane signaling pathway: the potential role of agonist-induced desensitization in the coronary artery of the rapid ventricular pacing-overdrive dog model of heart failure. 826 60


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