Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken to determine whether regular endurance running, of the type known to attenuate glucocorticoid-induced muscle atrophy, produces a reversal of the glucocorticoid-mediated suppression of myosin heavy chain (MHC) synthesis. Female rats were arbitrarily assigned to one of four groups. There were two sedentary groups that received either a vehicle (1% aqueous carboxymethyl cellulose) or cortisol acetate (100 mg/kg body wt) for 11 consecutive days and two exercise (treadmill running 29 m/min, 90 min/day, for 11 consecutive days) groups that received the activity simultaneously with either vehicle or steroid treatments. Protein synthesis measurements were performed by constant infusion of [3H]leucine. Fractional synthesis rates of MHC were determined from the leucyl-tRNA precursor pool, which was similar in all groups (range 2.85 +/- 0.32 to 3.51 +/- 0.43 dpm/pmol). Exercise prevented 30% of the plantaris muscle mass loss as the result of cortisol acetate treatment. MHC synthesis rates (%/day) in plantaris muscles of sedentary animals were reduced by glucocorticoid treatment to 65% (6.2/9.5) of the vehicle-treated group. Exercise did not alter this depression of MHC synthesis. The combination of exercise and glucocorticoid treatment reduced the calculated MHC breakdown rate (%/day) to 80% (-8.0/-10.1) of the rate resulting from hormone treatment alone and 60% (-8.0/-13.3) of the rate resulting from exercise alone. These results show that endurance exercise does not reverse the glucocorticoid inhibition of MHC synthesis in muscle but may act through reducing MHC breakdown.
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PMID:Myosin heavy chain turnover and glucocorticoid deterrence by exercise in muscle. 260 37

Hypertrophy of isolated adult feline cardiac muscle cells may be induced in culture by either alpha- or beta-adrenergic agonists. However, it has been shown previously that each of these agonists activate different subsets of immediate-early response genes and have different effects on expression of "fetal" protein isoforms and stimulation of protein synthesis. Moreover, in adult feline heart cells, beta-adrenergic agonists, such as isoproterenol, activate sustained synchronous beating and sarcomeric reorganization while alpha-adrenergic agonists, such as phenylephrine, do not. The objective of the present study was to determine whether these differences in proximal signaling events converged in a common signal pathway during activation of contractile protein synthesis. By direct comparisons of actin and myosin heavy chain (HC) synthesis and accumulation following isoproterenol and phenylephrine, it was determined that both agonists stimulate a coordinated accumulation of these proteins during cardiomyocyte growth. However, each agonist stimulated a very different program of contractile protein synthesis. During phenylephrine-induced hypertrophy, actin and myosin HC syntheses were rapidly and coordinately activated and continuously maintained at rates 10-25% greater than untreated cultures. The pattern of myosin HC synthesis following isoproterenol was very much more complex with periods during which it was as much as 40% greater or 25% less than in control cultures. Furthermore, there was no correlation between rates of actin and myosin HC synthesis following isoproterenol. It was concluded that actin and myosin HC syntheses and accumulation were regulated independently and in a very different manner following isoproterenol or phenylephrine. Since protein accumulation was not correlated with synthesis rates during development of hypertrophy, it was also concluded that post-translational mechanisms played a significant role in the maintenance of contractile protein stoichiometry during beta-adrenergic/beating-induced hypertrophy. Myosin HC synthesis also appeared to be independently regulated during cardiomyocyte atrophy induced by the calcium channel blocker nifedipine. Unlike the case in hypertrophy, however, protein balance was not maintained in nifedipine, and the depression of myosin HC synthesis and loss of myosin HC content were much greater than in the case of other contractile proteins.
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PMID:Myosin heavy chain synthesis is independently regulated in hypertrophy and atrophy of isolated adult cardiac myocytes. 792 58

Using an adult mouse aortic-banded model of pressure-overload hypertrophy and isolated cardiomyocyte mechanics studies, we examined the hypothesis that contractile depression is due to altered cardiac contractile proteins rather than changes in left ventricular (LV) geometry, loading, or the extracellular matrix. FVB mice were banded at the transverse aortic arch or sham operated and studied after 7 days. In nine animals the gradient across the aortic band averaged 47 +/- 4 mmHg. Compared with sham-operated controls, banded animals had increased LV weight-to-body weight ratio (2.8 +/- 0.1 and 3.5 +/- 0.1, respectively; P = 0.035). Left ventricles from additional age-matched groups of mice that underwent identical surgical procedures were examined for altered transcriptional control of myosin heavy chains (MHCs). beta-MHC protein content increased (15 +/- 2%) vs. shams (3.8 +/- 2%; P = 0.004). Dot blots of LV RNA showed a corresponding increase in beta-MHC transcripts in banded animals (15.8 +/- 2%) vs. controls (5.7 +/- 2%; P = 0.012). Contractile performance was assessed using enzymatically disaggregated isolated LV myocytes paced at 0.5 Hz. There was no difference in percentage myocyte shortening between banded (8.6 +/- 0.5%) and control (9.1 +/- 0.5%) animals. However, maximal velocity of contraction was depressed after aortic banding (129 +/- 11 vs. 233 +/- 28 microns/s; P = 0.007), as was velocity of relaxation (105 +/- 11 vs. 188 +/- 22 microns/s; P = 0.007). These results suggest that depressed myocyte contractility after induction of pressure-overload hypertrophy in aortic-banded mice may be, in part, a consequence of transcriptional upregulation of the beta-MHC.
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PMID:Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice. 804 5

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.
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PMID:The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. 868 57

Myofibrillar but not actomyosin ATPase is depressed in failing myocardium from patients with dilated cardiomyopathy. Since there is a similar depression of myofibrillar ATPase in mitral regurgitation myocardium, we investigated whether or not the hydrolytic and mechanical performances of myosin are altered by comparing the maximal actomyosin ATPase activity and the in vitro myosin motility of myocardial myosin from patients with mitral regurgitation heart failure with that of patients with normal ventricular function. The results show that there is no significant difference (P > .05) between nonfailing and failing values for either the maximal actomyosin ATPase activity (0.3 s-1.head-1) or the myosin motility (1 micron/s). These observations suggest that changes, other than in the myosin heavy chain, contribute to the altered myocardial performance in mitral regurgitation myocardium.
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PMID:Maximal actomyosin ATPase activity and in vitro myosin motility are unaltered in human mitral regurgitation heart failure. 875 98

The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypothyroidism or hyperthyroidism. Triiodothyronine (T3)-induced changes in cardiac function can result from direct or indirect T3 effects. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independently of nuclear T3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. The T3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T3 increases the heart transcription of the myosin heavy chain (MHC) alpha gene and decreases the transcription of the MHC beta gene, leading to an increase of myosin V1 and a decrease in myosin V3 isoenzymes. Myosin V1, which is composed of two MHC alpha, has a higher myosin ATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an increased velocity of contraction. T3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum (SR). This T3 effect results from T3-induced increases in the level of the mRNA coding for the SR calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the SR. Overall, T3 leads to an increase in ATP consumption in the heart. In addition, less chemical energy of ATP is used for contractile purposes and more of it goes toward heat production, which causes a decreased efficiency of the contractile process in the hyperthyroid heart. The pathophysiologic basis for myxedema is the opposite of that discussed for the hyperthyroid heart. In addition to decreased direct effects of thyroid hormone in cardiac myocytes, indirect effects occur through decreases in peripheral oxygen consumption and changes in hemodynamic parameters. Myofibrillar swelling with loss of striation and interstitial fibrosis occurs on histologic examination of hypothyroid hearts. In addition, accumulation of mucopolysaccharide substances (Glycosaminoglycans) can be demonstrated. On electron microscopic examination, mitochondria show disruption and lipid inclusion. Cardiac papillary muscle obtained from animals with hypothyroidism shows a depression of the force velocity curve and reduced rate of tension development, indicating significant contractile abnormalities. In patients with hypothyroidism, a true enhanced incidence of hypertension (increased peripheral vascular resistance) has been found. In addition, hypercholesterolemia and impairment of fatty acid mobilization are associated with myxedema and present additional risk factors for the development of atherosclerotic cardiovascular disease.
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PMID:[Cardiovascular effects of thyroid hormones]. 906 69

To elucidate cellular mechanisms of myocardial depression in Pseudomonas sepsis the effects of sublethal concentrations of P. aeruginosa exotoxin A--a main virulence factor--were studied in cultured neonatal rat cardiomyocytes. It is known that this toxin exerts its pathogenic effect by inhibition of protein synthesis via ADP-ribosylation and thereby inactivation of elongation factor 2 (EF-2). Within 48 72 h, half maximal inhibition of protein synthesis occurs at 4-10 ng/ml. The toxin prevents the beta-adrenoceptor(AR)-mediated myosin heavy chain isozyme shift (V3/V1), while the T3-induced myosin shift is not suppressed. While beta 1-AR-downregulation by excess of norepinephrine (NE) is not affected, protein synthesis-dependent receptor upregulation in the recover period after removal of NE is completely suppressed by P. aeruginosa exotoxin A. Thus, a non-lethal, partial inhibition of global cellular protein synthesis by P. aeruginosa exotoxin A: (1) completely prevents beta 1-AR-mediated myosin isozyme shift and beta-AR upregulation: (2) sustains the cardiomyocytes in a catecholamine-refractory contractile state in the recovery period after catecholamine desensitization: (3) suggests cellular mechanisms by which P. aeruginosa exotoxin A might impair heart function in Pseudomonas sepsis: and (4) may help reveal the possible influence of endogenous inhibitors of EF-2.
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PMID:Partial inhibition of protein synthesis by Pseudomonas exotoxin A deranges catecholamine sensitivity of cultured rat heart myocytes. 914 Aug 36

1. The effects of ventricular myosin heavy chain (MHC) composition on the kinetics of activation and relaxation were examined in both chemically skinned and intact myocardial preparations from adult rats. Thyroid deficiency was induced to alter ventricular MHC isoform expression from approximately 80% alpha-MHC/20% beta-MHC in euthyroid rats to 100% beta-MHC, without altering the expression of thin-filament-associated regulatory proteins. 2. In single skinned myocytes, increased expression of beta-MHC did not significantly affect either maximal Ca2+-activated tension (P0) or the Ca2+ sensitivity of tension (pCa50). However, unloaded shortening velocity (V0) decreased by 80% due to increased beta-MHC expression. 3. The kinetics of activation and relaxation were examined in skinned multicellular preparations using the caged Ca2+ compound DM-nitrophen and caged Ca2+ chelator diazo-2, respectively. Myocardium expressing 100% beta-MHC exhibited apparent rates of submaximal and maximal tension development (kCa) that were 60% lower than in control myocardium, and a 2-fold increase in the half-time for relaxation from steady-state submaximal force. 4. The time courses of cell shortening and intracellular Ca2+ transients were assessed in living, electrically paced myocytes, both with and without beta-adrenergic stimulation (70 nM isoproterenol (isoprenaline)). Thyroid deficiency had no affect on either the extent of myocyte shortening or the resting or peak fura-2 fluorescence ratios. However, induction of beta-MHC expression by thyroid deficiency was associated with increased half-times for myocyte shortening and relengthening and increased half-time for the decay of the fura-2 fluorescence ratio. Qualitatively similar results were obtained in both the absence and the presence of beta-adrenergic stimulation although the beta-agonist accelerated the kinetics of the twitch and the Ca2+ transient. 5. Collectively, these data provide evidence that increased beta-MHC expression contributes significantly to the observed depression of contractile function in thyroid deficient myocardium by slowing the rates of both force development and force relaxation.
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PMID:Role of myosin heavy chain composition in kinetics of force development and relaxation in rat myocardium. 978 68

Energy-rich phosphates, [ATP]/[ADPfree] ratios, and the myosin heavy chain (MHC) complement were determined in single fibres from normal rabbit muscles, and in fibres isolated from tibialis anterior muscle undergoing fast-to-slow conversion by chronic low-frequency stimulation (CLFS). In normal muscles, energy-rich phosphate contents and [ATP]/[ADPfree] ratios could thus be assigned to different MHC-based fibre types. Phosphocreatine (PCr) contents and [ATP]/[ADPfree] ratios differed markedly between fast- and slow-twitch fibres, as well as within the fast fibre subtypes. Both magnitudes were approximately twofold higher in the fastest (type IIB) fibres as compared to the slowest (type I) fibres. According to PCr contents and [ATP]/[ADPfree] ratios pure and hybrid fibres were aligned in an order similar to that determined by their contractile properties and myofibrillar ATPase activities. CLFS for up to 30 days induced pronounced decreases in PCr and [ATP]/[ADPfree] which attained levels twofold lower than in normal slow-twitch fibres. In both normal and stimulated muscles, PCr and [ATP]/[ADPfree] ratios were correlated, indicating their equilibrium in the different fibre types. The relationship detected between MHC isoform expression and the [ATP]/[ADPfree] ratio suggests that the drastic and persistent depression of the cellular energy state may act as an important signal initiating fast-to-slow transformation processes in muscle fibres.
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PMID:Energy state and myosin heavy chain isoforms in single fibres of normal and transforming rabbit muscles. 979 14

In this study alterations are characterized which occur, in myocardial force development morphological appearance and protein composition, during the development of cardiac hypertrophy and heart failure in monocrotaline (MCT) treated rats. The transition from cardiac hypertrophy to heart failure was studied by comparing the results from control (CON) and two MCT groups (40 and 44 mg/kg body weight). The three experimental groups consisted of at least five animals each. Parameters studied were: body weight (measured daily), lung/body weight ratio, right ventricular wall volume and thickness, and force development in thin right ventricular trabeculae at 27 degrees C, using different extracellular calcium concentrations and pacing frequencies. MCT injection resulted in marked right ventricular hypertrophy and heart failure as evidenced by an up to 2-fold increase in lung/body weight ratio and a 1.7-fold increase in wall volume. The MCT groups showed a negative force-frequency relation and maximum force was up to 2-fold less than in the CON group. Protein analysis by means of one- and two-dimensional gel electrophoresis revealed a marked (7-fold) up-regulation of the slow myosin heavy chain isoform as well as a 4.5-fold increase in the content of the cytoskeletal protein desmin, whereas the mitochondrial protein ATP-synthase content was reduced. Hence MCT-induced cardiac hypertrophy and heart failure result in altered cellular calcium handling, depression of maximum force output, an increase in the economy of myocardial contraction and changes in cytoskeletal structure and energy supply.
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PMID:Myocardial force development and structural changes associated with monocrotaline induced cardiac hypertrophy and heart failure. 1236 90


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