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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal rat cardiocytes were infected with a recombinant adenovirus type 5 containing the SV40 early promoter-Gsa fusion gene in order to evaluate the presumed role of the stimulatory G-protein (Gs) in hypertrophy of myocardial cells. In vitro infection of myocardial cells with the recombinant adenovirus induced a 79-fold increase in Gs alpha mRNA and a 5-fold increase in Gs alpha protein, which was accompanied by a pronounced cell hypertrophy but not cell proliferation. Interestingly, adenovirus-infected cells displayed features of cell hypertrophy, an increase in sodium fluoride-stimulatible membrane-bound activity of adenylyl cyclase, and an enhanced beta-adrenergic sensitivity irrespective of the presence or absence of the SV40 early promoter-Gs alpha fusion gene in the virus. While the recombinant adenovirus induced a 5-fold versus 3-fold increase for plain adenovirus in cellular Gs alpha, membrane-bound Gs alpha was increased about 2-fold in both instances, which can explain similar increase in the G-protein-modulated adenylyl cyclase activity determined in membranes derived from myocardial cells infected with both types of the virus. It is concluded that adenovirus infection per se can lead to overexpression of Gs alpha and myocardial hypertrophy and thus may be of importance in the pathogenesis of virus-induced cardiomyopathy.
Biochem Mol Biol Int 1994 Nov
PMID:Adenovirus infection of myocardial cells induces an enhanced sensitivity to beta-adrenergic agonists by increasing the concentration of the stimulatory G-protein. 770 16

Extrahepatic synthesis and localization of angiotensinogen have been described in animals, thus establishing the tissue renin-angiotensin system. We examined angiotensinogen messenger RNA synthesis by northern blotting. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies using a specific antibody to angiotensinogen revealed a stronger reaction in the endocardial layer of the human left ventricle, than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Furthermore, our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. We examined the participation of the collagen in the occurrence and progression of cardiomyopathy. The acetic acid solubility of collagen and reducible crosslink decreased in cardiomyopathic hamsters as the fibrosis progressed, but was unchanged in controls. These findings indicate that in the early phase of cardiomyopathy the extracellular matrix of the myocardium is similar to immature tissues. In the later phase, the matrix resembles that of hard tissues, and is insoluble. Furthermore, we examined the relationship between angiotensin II and collagen synthesis. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6-fold greater than that in Wistar-Kyoto rats. The responsiveness of collagen production to Ang II was significantly enhanced in SHR. This effect was angiotensin receptor-specific, because it was blocked by the competitive inhibitor. These results indicate angiotensin II may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.
J Mol Cell Cardiol 1995 Jan
PMID:Renin-angiotensin system in failing heart. 776 Mar 44

Human cardiomyopathy has been extensively studied in the last decade, and knowledge of the functional and structural alterations of the heart has grown. However, understanding of the pathogenesis has come mostly from experimental studies. A number of work have been designed to elucidate if alterations of the contractile apparatus of cardiac cells contribute to the impairment of heart mechanics in cardiomyopathies. As well, an important question is to be solved: whether energy supply of the contraction-relaxation cycle is sufficient in the myopathic heart. Use of cardiac fibers skinned by different techniques allows to evaluate functional ability of myofibrils, mitochondria and bound creatine kinase which plays an important role in cardiomyocyte energy metabolism. The data presented in this chapter show that experimental cardiomyopathies of various types have some common features. These are an increase in calcium sensitivity of myofibrils and a depression of functional activity of mitochondrial creatine kinase. Possible mechanisms and physiological significance of these changes are discussed.
Mol Cell Biochem
PMID:In situ study of myofibrils, mitochondria and bound creatine kinases in experimental cardiomyopathies. 780 60

Doxorubicin (Dox) is a widely used antineoplastic agent. Irreversible cardiomyopathy is a serious and dose-limiting side effect after chronic administration. The iron chelating bispiperazinedione ICRF-187 is currently the only drug which affords protection against Dox-induced cardiotoxicity. To compare the protective value of structurally unrelated iron chelators, isolated mice atria were exposed to Dox (30 microM) and either the hydroxamate desferrioxamine (DFO, 200 and 500 microM), EDTA (200 microM) or the hydroxypridones CP44 (200 microM), CP51 (200 microM), and CP93 (200 microM) and ICRF-187 (200 and 500 microM). The nitroxide TEMPO (5 mM) lacks iron chelating properties but was used to prevent redox cycling or iron and scavenge superoxide. All iron chelators, except EDTA. CP93 and CP44, were modestly protective against a Dox-induced decrease in contractile force. As a single agent the hydroxypridones decreased atrial contractile force. At a concentration of 200 microM, DFO was the most effective protector of the chelators tested. However, this effect disappeared when a concentration of 500 microM was used. This in contrast to ICRF-187 for which a concentration-dependent inhibition of Dox-induced decrease in contractile force was observed. TEMPO exerted a biphasic response consisting of a two-fold increase in contractile force, followed by a decrease in force and irregular contractions. In this model TEMPO lacked any perspective as a cardioprotectant. We conclude that at 200 microM. DFO was the most effective agent to afford protection against Dox-mediated atrial malfunction. However, at 500 microM, DFO was not effective whereas ICRF-187 afforded partial protection. Hydroxipyridones were found to be of limited value because of a negative inotropic effect on the isolated atria.
J Mol Cell Cardiol 1994 Sep
PMID:Comparison of different iron chelators as protective agents against acute doxorubicin-induced cardiotoxicity. 781 60

L-type calcium currents were studied in ventricular myocytes isolated from non-failing hearts, i.e. donor hearts not suitable for transplantation, and from severely failing hearts, i.e. explanted hearts of organ recipients, in order to identify possible alterations of the currents in cardiomyopathy. Human atrial myocytes were investigated for comparative purposes. As deficient production of cyclic AMP might contribute to the development of cardiac failure, the responses to forskolin, a direct stimulator of adenylyl cyclase, were also studied. The patch-clamp technique was applied in the single electrode whole-cell mode. Calcium currents were similar in myocytes from non-failing and failing hearts: Maximum current-densities were 3.8 v 3.1 pA/pF, and 2.2 pA/pF in atrial cells. In human ventricular cells, threshold was at -33 mV, maximum at +6 mV and reversal potential at about +50 mV, potentials of half-maximum steady-state inactivation -24 mV and -18 mV. The slopes of steady-state inactivation curves were +4.1 mV in myopathic and +5.5 mV in non-failing cells. In all myocytes the current inactivated with two time constants, a fast one with weak and a slow one with pronounced potential dependency. Ventricular or atrial myocytes from patients pretreated with calcium antagonists and untreated did not differ in current density or steady-state inactivation. Forskolin (0.5 microM) increased calcium currents in myocytes from non-failing and failing hearts to the same extent (by 143 and 150%). While beta-adrenoceptor numbers are reported to decline in severely failing myocardium, our data do not suggest that alterations of the properties of calcium currents contribute to the pathophysiology of heart failure, though the number of investigated hearts is limited due to restricted access to non-failing cardiac tissue. No evidence for impairment of the signal transduction cascade beyond the level of GTP binding proteins was found.
J Mol Cell Cardiol 1994 Oct
PMID:L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. 786 91

Electromechanical responsiveness to angiotensin II (Ang II) receptor stimulation in ventricular myocardium and myocytes of hypertrophic cardiomyopathic Syrian hamsters (BIO 14.6) was examined and compared with that in preparations of normal hamsters (F1B) using conventional microelectrode and patch clamp techniques. Action potential duration (APD) and developed tension (DT) corrected for the cross-sectional area of the papillary muscles of 14-20 week-old BIO 14.6 hamsters were significantly smaller than those in preparations of age-matched normal hamsters. An Ang II (1 microM)-induced increase in DT in BIO 14.6 papillary muscles (24.7 +/- 11.0%) was significantly smaller than that in F1B papillary muscles (53.8 +/- 8.5%), which was associated with a smaller increase in APD in BIO 14.6 papillary muscles. In ventricular myocytes of both BIO 14.6 and F1B hamsters. Ang II increased the calcium current (ICa) following a transient decrease in ICa. However, the magnitude of the Ang II-induced increase in ICa in BIO 14.6 myocytes (35.5 +/- 7.5%) was significantly smaller than that in F1B myocytes (86.0 +/- 19.7%), suggesting a causal relationship between ICa and mechanical response to Ang II in these hamsters. The depressed responsiveness to Ang II receptor stimulation in hypertrophic cardiomyopathic hamster is in a marked contrast with the enhanced responsiveness to alpha 1-adrenergic stimulation, which was demonstrated by previous studies, and may be one of adaptational changes to the activated renin-angiotensin system in the cardiomyopathy.
J Mol Cell Cardiol 1994 Nov
PMID:Depressed responsiveness to angiotensin II in ventricular myocytes of hypertrophic cardiomyopathic Syrian hamster. 789 67

An increase of Gi alpha-related pertussis toxin substrates has been observed in the failing myocardium. In order to quantify the protein expression of Gi alpha directly, we developed a fast radioimmunoassay using the iodinated synthetic peptide 125I-KENLKDCGLF. beta-adrenoceptors were studied with 125I-cyanopindolol binding for comparison. Immunoblot experiments using recombinant G-protein alpha-subunits showed that DS4 immunostained the G-protein alpha-subunits with a rank order of potency rGi alpha 1 = rGi alpha 2 > rGo alpha >> rGi alpha 3. The G-protein alpha-subunits recognized by DS4 in human ventricular membranes comigrated with rGi alpha 1 and rGi alpha 2. The radioimmunoassay had a sensitivity of 2.5 micrograms/ml transducin alpha with an interassay variation of less than 10%. The non-labelled peptide selectively competed with the myocardial 40 kDa membrane protein for binding to the antiserum DS4. Radioimmunochemical quantification of Gi alpha from cardiac membranes showed that in left ventricular membranes (LV) from dilated cardiomyopathy (DCM), there was an increase of Gi alpha by 138.5% when related to mg protein and 135% when related to 3H-ouabain binding sites as membrane marker. In LV from ischaemic cardiomyopathy (ICM), the increase was smaller (58.4%) when related to mg protein compared to the increase of Gi alpha when related to 3H-ouabain binding sites as membrane marker (155% v NF). In contrast, in the right ventricles (RV) there was no increase of Gi alpha in ICM or DCM. The numbers of beta-adrenoceptors were reduced in RV and LV of both, ICM and DCM. It is concluded that the radioimmunoassay may become an important tool for studying the expression of Gi alpha-protein levels and changes thereof in pathological conditions. The amount of immunodetectable Gi alpha-proteins is increased in failing LV due to DCM and ICM but not in RV, while beta-adrenoceptor down-regulation occurred in RV and LV in both conditions. These findings might indicate that the liability of the LV but not of RV to express Gi alpha-proteins may be increased in predominant LV heart failure. Alternatively, the underlying mechanism, e.g. sympathetic activation, may be regulated locally in the failing heart producing different changes in adjacent chambers.
J Mol Cell Cardiol 1994 Feb
PMID:Radioimmunochemical quantification of Gi alpha in right and left ventricles from patients with ischaemic and dilated cardiomyopathy and predominant left ventricular failure. 800 75

Adriamycin has been widely used as an anticancer drug, but its clinical use is limited by a dose-dependent cardiac toxicity. Proposed mechanisms for the adriamycin-induced cardiomyopathy include increasing the Ca current, inhibiting the Na/Ca exchange and dysfunction of the sarcoplasmic reticulum (SR). Using the whole cell voltage clamp technique in single isolated atrial and ventricular myocytes of the rabbit, we have investigated the effect of adriamycin on various current systems which are related to regulating intracellular Ca concentration: the Ca current, the Na/Ca exchange current and [Ca2+]i-dependent currents (ouabain-induced transient inward current and the inward tail current). Adriamycin, 0.05 mg/ml, increased Ca current (L-type) by 61%. Adriamycin inhibited the inward tail current in a dose-dependent manner between 0.02 and 0.1 mg/ml and when low concentration was used the effect was reversible. Ouabain-induced transient inward current was also suppressed by 0.05 mg/ml adriamycin. Na/Ca exchange current which is partly responsible for inducing [Ca2+]i-dependent currents was, however, not affected by adriamycin, suggesting that the effect adriamycin on [Ca2+]i-dependent currents is due to inhibition of SR function. From these results it is suggested that the increase of Ca current and inhibition of SR function cause adriamycin-induced cardiac toxicity: SR dysfunction not only causes a decrease of myocardial contractility, it can also accelerate the Ca overload process which might originate from the increase of Ca current.
J Mol Cell Cardiol 1994 Feb
PMID:Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit. 800 77

To investigate the microdynamics and the structural architecture of the membrane phospholipid bilayer during the course of cardiomyopathy, membrane fractions were prepared from hearts of cardiomyopathic Syrian hamsters (BIO 14.6) aged 4, 18 and 31 weeks and compared with age-matched control hamsters (F1b). Membrane cholesterol, phospholipids and phospholipid fatty acids were measured by thin-layer chromatography, gas-liquid chromatography and high performance liquid chromatography. Microdynamics of the phospholipid bilayer were determined by a nanosecond fluorometer using pulsed excitation of a fluorescent probe, diphenyl-hexatriene. At the age of 4 weeks, there was no difference in lipid compositions and microdynamics between the BIO 14.6 and F1b. At the age of 18 weeks, saturated fatty acids, 18:0 and 22:0 increased and 20:0, 20:2 and 32:4 decreased in the BIO 14.6. At the age of 31 weeks, adding to the above changes in phospholipid fatty acids, unsaturated fatty acids 20:4 and 22:6 decreased, moreover membrane phospholipids, especially phosphatidylinositol and phosphatidylethanolamine significantly decreased. The viscosity and the wobbling angle of phospholipid molecules were decreased significantly. We have previously demonstrated that intracellular Ca2+ accumulation might be responsible for the pathogenesis of cardiomyopathy. Thus, we conclude that cardiomyopathic membrane may alter its structure and function with age. These alterations in cell membranes might be involved in the cardiac hypertrophy and dysfunction through impaired Ca2+ handling in cardiomyopathic hamsters.
J Mol Cell Cardiol 1994 Feb
PMID:Microdynamics of the phospholipid bilayer in cardiomyopathic hamster heart cell membrane. 800 82

Calcium overload has been linked to the development of cardiomyopathy in the cardiomyopathic (CM) hamster, but the site or sites of the lesion remain obscure. To determine whether the number of sarcoplasmic reticulum (SR) calcium release channels (ryanodine receptors) changes in the CM heart, we compared the density (Bmax) and affinity (Kd) of [3H]-ryanodine binding sites in heavy SR fractions from 40-65 day-old normal and CM hamster hearts. Results showed that the Bmax was significantly increased in CM heart when compared to normal (Bmax = 2489 +/- 159 fmol/mg protein in normal heart and 3360 +/- 223 fmol/mg protein in CM heart, mean +/- S.E., P = 0.01). [3H]-Ryanodine bound to a single, high affinity site in SR from both normal and CM hearts; values for Kd were similar in both groups. Sensitivity of [3H]-ryanodine binding to Ca2+ was unchanged, but the density of binding was increased at all Ca2+ concentrations which potentiated binding in CM heart. Similarly, potentiation of [3H]ryanodine binding by ATP and inhibition of binding by Mg2+ were intact in membranes from CM heart. Results demonstrate that the density [3H]-ryanodine receptors is increased in SR from CM hearts early in the development of cardiomyopathy, although the properties of these receptors are unchanged. This suggests an increase in the amount or velocity of Ca2+ release from SR may contribute to the development of Ca2+ overload in this model of cardiomyopathy.
J Mol Cell Cardiol 1994 Mar
PMID:Density of ryanodine receptors is increased in sarcoplasmic reticulum from prehypertrophic cardiomyopathic hamster heart. 802 15


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