Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To characterize interventions resulting in 'physiological' growth of the heart, Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) had hyperthyroidism induced (0.05 mg.kg-1.day-1 triiodothyronine for 6 days) or were treated with a high dose of the carnitine palmitoyltransferase-1 inhibitor, etomoxir (15 mg.kg-1.day-1 for 5 weeks). Etomoxir increased cardiac growth evenly, but hyperthyroidism resulted in an over-proportional higher right ventricular weight. Both interventions increased the proportion of the myosin isozyme V1. The rate of sarcoplasmic reticulum (SR) Ca2+ uptake was increased to a greater extent in hyperthyroid rats than in etomoxir-treated rats (P < 0.05). Left ventricular levels of immunoreactive phospholamban (semiquantitative ELISA) were moderately decreased (P < 0.05) in hyperthyroid rats but not in etomoxir-treated rats. The protein kinase A-catalyzed in vitro 32P-incorporation into the SR Ca2+ pump modulator phospholamban was greatly reduced (P < 0.05) in hyperthyroid rats, indicating an increased in vivo phosphorylation. Etomoxir did not affect phospholamban phosphorylation in WKY rats. Thus, both a higher in vivo phospholamban phosphorylation state and a greater number of active Ca2+ pumps contributed to an increased rate of SR Ca2+ uptake in hyperthyroidism. The etomoxir treatment primarily increased the number of active Ca2+ pumps. A scheme is proposed focusing on long-term vs short-term regulation of the SR Ca2+ pump/phospholamban system in diseased states.
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PMID:Differential influences of carnitine palmitoyltransferase-1 inhibition and hyperthyroidism on cardiac growth and sarcoplasmic reticulum phosphorylation. 755 65

To define determinants of subcellular structures of heart, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated for 5 wk with 15 mg.kg-1.day-1 etomoxir [reduces mitochondrial carnitine palmitoyltransferase-1 (CPT-1) activity and fatty acid synthesis]. To bypass CPT-1 inhibition, etomoxir-treated rats were fed a medium-chain fatty acid (MCFA) diet. Etomoxir induced a proportionate growth of heart, which could partially (WKY, P < 0.05) or completely (SHR, P < 0.05) be prevented by the MCFA diet. Also the etomoxir-induced increase in myosin V1 was partially prevented (P < 0.05). Etomoxir increased (P < 0.05) rate of sarcoplasmic reticulum (SR) Ca2+ uptake of WKY and SHR ventricular homogenates in the presence or absence of the SR Ca2+ release inhibitor ruthenium red. The MCFA diet resulted in SR Ca2+ uptake rates that were in between those of etomoxir-treated and untreated rats. The in vitro 32P incorporation into phospholamban and troponin I did not differ significantly in WKY. Etomoxir induced, however, an increase (P < 0.05) in the phosphorylated intermediate of the Ca2+ adenosinetriphosphatase in WKY that was prevented by the MCFA diet. In SHR, etomoxir increased the in vitro phospholamban phosphorylation, which was reduced compared with WKY. The data show that myosin and SR are affected by a chronically altered substrate utilization of heart.
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PMID:Dietary medium-chain triglycerides can prevent changes in myosin and SR due to CPT-1 inhibition by etomoxir. 757 66

To characterize the effect of an altered substrate utilization for cardiac sarcoplasmic reticulum (SR) Ca2+ transport, normotensive rats were treated for 5 wk with 15 mg.kg-1.day-1 enantiomeric etomoxir, which inhibits mitochondrial carnitine palmitoyltransferase-1 (CPT-1) and fatty acid synthesis. Ca2+ uptake rates of left and right ventricular homogenates were differentially (P < 0.05, two-way analysis of variance) increased by 38 and 13%, respectively. Increased (P < 0.05) transport rates were also observed in the presence of ryanodine. The differences were considerably reduced in the protein kinase A-stimulated state. The levels of phosphorylated phospholamban (PLB) and troponin I as well as immunoreactive PLB were not affected. By contrast, phosphoenzyme levels (E-P) of the SR Ca2+ pump were increased in left ventricular (LV) homogenates. Values of LV E-P and Ca2+ uptake were linearly correlated (P < 0.05) with the myosin V1 proportions in control (31.7 +/- 1.8% V1) and treated (58.3 +/- 2.5% V1) rats. Thus in the left ventricle the metabolic influences have a coordinated action on two distinct proteins involved in relaxation or contraction. The chamber-specific differences in SR function suggest a more pronounced effect of etomoxir in functional states characterized by a reduced Ca2+ transport rate and myosin V1 proportion.
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PMID:CPT-1 inhibition by etomoxir has a chamber-related action on cardiac sarcoplasmic reticulum and isomyosins. 781 Jul 10

Recent studies have shown that beta 2-adrenergic receptor (beta 2-AR)-stimulated increases in the intracellular Ca2+ (Cai) transient and contraction in cardiac myocytes are dissociated from the increase in adenosine 3',5'-cyclic monophosphate (cAMP) level and are not accompanied by an increase in phospholamban phosphorylation, an acceleration in relaxation, or a reduction in myofilament Ca2+ response. Thus we hypothesized that the beta 2-AR modulation of cardiac excitation-contraction (EC) coupling may be mediated by either a cAMP-independent mechanism or a compartmentalized cAMP pathway. To directly distinguish between these two possibilities, the responses of the L-type Ca2+ current (ICa), Cai transient, and contraction to beta 2-AR as well as to beta 1-AR stimulation were examined in rat ventricular myocytes in the presence or absence of specific inhibitory cAMP analogs, Rp diastereomers of adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) and 8-(4-chlorophenylthio)-cAMP (Rp-CPT-cAMPS). As expected, the positive inotropic effect induced by an adenylyl cyclase activator, forskolin (2 x 10(-7) M), or a beta 1-AR agonist, norepinephrine (5 x 10(-8) M) plus prazosin (10(-6) M), was completely blocked by Rp-CPT-cAMPS. More importantly, the responses of ICa, Cai transient, and contraction to beta 2-AR stimulation by zinterol (10(-5) M) or isoproterenol plus a selective beta 1-AR antagonist, CGP-20712A, were also entirely abolished by Rp-cAMPS (in the patch-pipette solution) or Rp-CPT-cAMPS (in the bath solution). In pertussis toxin-treated cells, although the response of cAMP was not altered, the beta 2-AR-stimulated increase in contraction amplitude was markedly enhanced and accompanied by a hastened relaxation, resulting in a tight association between cAMP and contraction. These results indicate that beta 2-AR modulation of cardiac excitation-contraction coupling requires cAMP. The dissociation of beta 2-AR-stimulated cAMP production and regulation of myofilament and sarcoplasmic reticulum functions is attributable to a functional compartmentation of the cAMP-dependent signaling due to an activation of beta 2-AR-coupled Gi and/or G(o).
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PMID:Localized cAMP-dependent signaling mediates beta 2-adrenergic modulation of cardiac excitation-contraction coupling. 932 56

Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. The hypothesis was examined that pressure overloaded hearts fail to increase SR Ca(2+) uptake rate proportionally to the hypertrophy and that carnitine palmitoyltransferase-1 inhibition by etomoxir ((+/-)-ethyl 2[6(4-chlorophenoxy)hexyl] oxirane-2-carboxylate) can counteract this process. Severe left ventricular pressure overload was induced in rats by constricting the ascending aorta for 8, 10, 14 and 28 weeks leading to cardiac hypertrophy (+62 - +103% of sham-operated rats) and pulmonary congestion. Homogenate oxalate-facilitated SR Ca(2+) uptake rate g wet wt(-1) was reduced (P<0.05) by 29.9+/-1.8% irrespective of phospholamban phosphorylation (in the presence of catalytic subunit of protein kinase A) and inhibition of SR Ca(2+) release channel by ruthenium red. SERCA2 protein level was reduced (P<0.05) by 30.4+/-0.8%. SR Ca(2+) uptake rate was inversely correlated (P<0.05) with left ventricular weight but was not affected by the occurrence of pulmonary congestion. Because SR Ca(2+) uptake rate of whole ventricles was not reduced, a hypertrophy proportional dilution of SR Ca(2+) uptake has to be inferred which precedes pulmonary congestion. Treatment with etomoxir (15 mg kg body wt(-1) day(-1) for 10 weeks) did not affect left ventricular weight but decreased (P:<0.05) the right ventricular hypertrophy related to pulmonary congestion. In parallel, SR Ca(2+) uptake rate of left ventricle and myosin isozyme V(1) were increased (P<0.05). Etomoxir represents a candidate approach for prevention of heart failure by inducing a hypertrophy proportional increase in SR Ca(2+) uptake rate.
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PMID:Sarcoplasmic reticulum function and carnitine palmitoyltransferase-1 inhibition during progression of heart failure. 1113 55

H9c2 myoblasts are a cell model used as an alternative for cardiomyocytes. H9c2 cells have the ability to differentiate towards a cardiac phenotype when the media serum is reduced in the presence of all-trans-retinoic acid (RA), creating multinucleated cells with low proliferative capacity. In the present study, we performed for the first time a transcriptional analysis of the H9c2 cell line in two differentiation states, i.e. embryonic cells and differentiated cardiac-like cells. The results show that RA-induced H9c2 differentiation increased the expression of genes encoding for cardiac sarcomeric proteins such as troponin T, or calcium transporters and associated machinery, including SERCA2, ryanodine receptor and phospholamban as well as genes associated with mitochondrial energy production including respiratory chain complexes subunits, mitochondrial creatine kinase, carnitine palmitoyltransferase I and uncoupling proteins. Undifferentiated myoblasts showed increased gene expression of pro-survival proteins such as Bcl-2 as well as cell cycle-regulating proteins. The results indicate that the differentiation of H9c2 cells lead to an increase of transcripts and protein levels involved in calcium handling, glycolytic and mitochondrial metabolism, confirming that H9c2 cell differentiation induced by RA towards a more cardiac-like phenotype involves remodeled mitochondrial function. PI3K, PDK1 and p-CREB also appear to be involved on H9c2 differentiation. Furthermore, complex analysis of differently expressed transcripts revealed significant up-regulation of gene expression related to cardiac muscle contraction, dilated cardiomyopathy and other pathways specific for the cardiac tissue. Metabolic and gene expression remodeling impacts cell responses to different stimuli and determine how these cells are used for biochemical assays.
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PMID:Gene Expression Profiling of H9c2 Myoblast Differentiation towards a Cardiac-Like Phenotype. 2612 Nov 49

In cardiac muscle, signaling through cAMP governs many fundamental cellular functions, including contractility, relaxation and automatism. cAMP cascade leads to the activation of the classic protein kinase A but also to the stimulation of the recently discovered exchange protein directly activated by cAMP (Epac). The role of Epac in the regulation of intracellular Ca2+ homeostasis and contractility in cardiac myocytes is still matter of debate. In this study we showed that the selective Epac activator, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate (8-CPT), produced a positive inotropic effect when adult rat cardiac myocytes were stabilized at low [Ca2+]o (0.5mM), no changes at 1mM [Ca2+]o and a negative inotropic effect when [Ca2+]o was increased to 1.8mM. These effects were associated to parallel variations in sarcoplasmic reticulum (SR) Ca2+ content. At all [Ca2+]o studied, 8-CPT induced an increase in Ca2+ spark frequency and enhanced CaMKII autophosphorylation and the CaMKII-dependent phosphorylation of SR proteins: phospholamban (PLN, at Thr17 site) and ryanodine receptor (RyR2, at Ser2814 site). We used transgenic mice lacking PLN CaMKII phosphorylation site (PLN-DM) and knock-in mice with an inactivated CaMKII site S2814 on RyR2 (RyR2-S2814A) to investigate the involvement of these processes in the effects of Epac stimulation. In PLN-DM mice, 8-CPT failed to induce the positive inotropic effect at low [Ca2+]o and RyR2-S2814A mice showed no propensity to arrhythmic events when compared to wild type mice myocytes. We conclude that stimulation of Epac proteins could have either beneficial or deleterious effects depending on the steady-state Ca2+ levels at which the myocyte is functioning, favoring the prevailing mechanism of SR Ca2+ handling (uptake vs. leak) in the different situations.
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PMID:Early effects of Epac depend on the fine-tuning of the sarcoplasmic reticulum Ca2+ handling in cardiomyocytes. 2903 82