Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Basic (b) fibroblast growth factor (FGF) mediates various biological responses including mitogenesis and angiogenesis by binding to specific cell surface receptors of the tyrosine kinase family. The bFGF receptor-1 FGFR1) exists in short and long isoforms due to alternate RNA splicing. Minor alterations in the amino acid sequence have also led to reports of different FGFR1 isoforms in different tissues even in the same species. In the absence of any sequence for heart FGFR1 and accumulating evidence for a role of bFGF in heart growth and differentiation, we cloned FGFR1 from embryonic mouse hearts. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to generate full-length short (2259 base pairs) and long (2526 base pairs) forms of FGFR1 cDNAs which generated 86 and 102 kDa proteins, respectively, following in vitro translation. Embryonic mouse heart FGFR1 differed by seven amino acids from the reported sequence for mouse neuroepithelial FGFR1 and appeared more similar to human placental FGFR1. A single FGFR1 transcript of approximately 4.3 kb was seen in RNA isolated from embryonic as well as adult mouse hearts. There was a decrease (approximately 8.5-fold) in FGFR1 RNA levels in the adult. The majority of FGFR1 transcripts in the adult as well as embryonic heart contained exon IIIc (FGFR1-IIIc) which is associated with isoforms that display the highest affinity for bFGF. However, the relative ratio of short versus long FGFR1 RNA expression was 0.5 in the embryonic heart compared to 5.9 in the adult heart. These results indicate that: (i) structurally distinct short and long FGFR1 isoform RNAs are expressed in the embryonic and adult heart; (ii) FGFR1-IIIc is the major form of receptor expressed in the embryonic as well as adult heart; (iii) the transition from the embryo to the adult stage is associated with a decrease but not absence of FGFR1 RNA expression; and (iv) long FGFR1-isoforms are more abundant in the embryo while short FGFR1 isoforms predominate in the adult.
J Mol Cell Cardiol 1994 Nov
PMID:Cloning and expression of fibroblast growth factor receptor-1 isoforms in the mouse heart: evidence for isoform switching during heart development. 789 69

High energy phosphates (HEP: ATP & phosphocreatine (PCr)) are to be considered under qualitative (free energy of hydrolysis) and quantitative (concentration) aspects. Energy charge is also a (normalized) concentration related parameter. Owing to high turnover rates concentration (HEP stores) provides sufficient energy only for 10 to 20 s in the case of interruption of supply. Utilization (without immediate supply) leads to rapid drop of free energy which--owing to the CK reaction--is indicated by rapid drop of PCr and the respective ratios. Critical reduction of free energy appears to be prevented by various protective mechanisms reflected in phenomena of early hypoxic failure, hibernating and stunning.
Basic Res Cardiol
PMID:Meaning of energetic parameters. 811 44

Although important strides have been made in related procedures, exercise ECG remains an invaluable tool in the initial assessment of coronary disease and yields a great deal of prognostic information. Access to limited health care resources often hinges on its outcome. Proper methodology is critical to patient safety and to obtain accurate results. The importance of patient education, physician interaction with the patient, skin preparation, and criteria for exclusion and termination cannot be overemphasized. A brief physical examination and 12-lead ECG in both the supine and standing positions should precede exercise testing. Few studies have correctly evaluated the relative yield or sensitivity and specificity of different electrode placements for exercise-induced shifts in the ST segment. The use of other leads in addition to V5 increases test sensitivity, but the specificity may be reduced. ST-segment changes isolated to the inferior leads are frequently false-positive responses. Vectorcardiographic and body surface mapping lead systems do not appear to offer any advantage over simpler approaches for clinical purposes. Changes caused by exercise electrode placement can be kept to a minimum by placing arm electrodes on the shoulders, off of the chest. The exercise protocol should be progressive, with even increments in speed and grade whenever possible. Smaller, even, and more frequent work increments are preferable to larger, uneven, and less frequent increases, because the former yield a more accurate estimation of exercise capacity. The value of individualizing the exercise protocol rather than using the same protocol for every patient has recently been emphasized by many investigators. The optimal test duration is from 8 to 12 minutes, and the protocol workloads should be adjusted to permit this duration. Because ramp testing uses small increments, it permits a more accurate estimation of exercise capacity and can be individualized for every patient to yield a targeted test duration. Target heart rates based on age should not be used because the relationship between maximal heart rate and age is poor and varies greatly. The Borg scale is a useful means of quantifying an individual's effort. Exercise capacity should not be reported in total time but rather as the VO2 or MET equivalent of the workload achieved. This permits comparison of the results between many different exercise testing protocols. Gas-exchange techniques can greatly supplement exercise testing by adding precision and reproducibility and increase the yield of information concerning cardiopulmonary function. Estimating work from treadmill or cycle ergometer workload introduces a great deal of error and variability.(ABSTRACT TRUNCATED AT 400 WORDS)
Cardiol Clin 1993 May
PMID:Exercise testing. Procedures and implementation. 850 47

The mitochondrial ATPase enzyme accounts for roughly 35-50% of the overall energy demand that leads to ATP depletion under conditions of severe myocardial ischemia. In larger mammalian hearts, this energy squandering action of the ATPase is modulated by an endogenous inhibitor protein. The present studies were undertaken to characterize the time course of inhibition of the mitochondrial ATPase in canine myocardium under conditions of severe regional ischemia in vivo. In addition, we determined if the energy sparing effects of ischemic preconditioning (PC) can be explained by persistent inhibition of the mitochondrial ATPase enzyme. The circumflex coronary artery was ligated for 1.5 min (n = 4), 5 min (n = 6), or 15 min (n = 5). In a separate group (n = 7), hearts were preconditioned by four 5-min periods of ischemia each followed by 5 min of reperfusion. Sub-mitochondrial particles were prepared from the sub-endocardial zone of the ischemic and non-ischemic regions and were assayed for oligomycin-sensitive ATPase activity. ATPase activity was reduced to about 79% at 1.5 min and to approximately 55% at 5 and 15 min of ischemia, relative to non-ischemic tissue from the same heart. The rate of HEP utilization slowed concurrently with the development of ATPase inhibition. In preconditioned myocardium, ATPase activity was not significantly different from control myocardium from the same heart. We conclude that the early inhibition of the mitochondrial ATPase activity slows the utilization of high energy phosphate and thereby serves as an important endogenous cardioprotective mechanism. Nevertheless, altered activity of the ATPase is not the explanation of the energy sparing effect of ischemic preconditioning.
J Mol Cell Cardiol 1996 Jan
PMID:Effect of reversible ischemia on the activity of the mitochondrial ATPase: relationship to ischemic preconditioning. 874 18

Vascular Endothelial Growth Factor (VEGF) is a specific endothelial mitogen and an important angiogenic factor in vivo, capable of inducing therapeutic angiogenesis when administered to ischemic myocardium. Suramin, originally developed as an anti-trypanosomal agent, was recently shown to exert an antiangiogenic action. We have tested the hypothesis, whether the antiangiogenic effect of suramin may be mediated via inhibition of VEGF function. Using cultured endothelial cells and a [3H]thymidine incorporation assay we were able to show, that the action of VEGF upon mitogenicity is inhibited by suramin in a dose-dependent manner. The same was true for inhibition of VEGF-induced chemotaxis of endothelial cells. Suramin inhibited VEGF-inducible tyrosine phosphorylation of KDR as determined by in vitro kinase assay. Moreover, suramin was shown to inhibit VEGF-induced tyrosine phosphorylation of KDR in intact cells, indicating an interaction of suramin with the VEGF-receptor KDR as the cause of its inhibitory activity. The antiangiogenic effect of suramin may be mediated-at least in part-by inhibition of VEGF function. Given the feasibility of in vivo use, suramin may be a valuable tool for investigating the functional role of angiogenesis in the cardiovascular system.
J Mol Cell Cardiol 1996 Jul
PMID:Suramin is a potent inhibitor of vascular endothelial growth factor. A contribution to the molecular basis of its antiangiogenic action. 884 39

Recently, three mammalian mitogen-activated protein (MAP) kinases, ERK, SAPK/JNK, and p38/HOG-1 have been identified, each with apparently unique signal transduction pathways. The p38 MAP kinase mediates an intracellular stress-activated signaling pathway by regulating down-stream molecules, such as MAP kinase-activated protein (MAPKAP) kinase 2. To study the tissue specificity of MAPKAP kinase 2, mRNA blots containing multiple human tissues were hybridized with a specific oligonucleotide probe corresponding to human MAPKAP kinase 2. The Northern blot analysis revealed that two mRNA species of MAPKAP kinase 2, with sizes of 4.8 and 3.3 kb, were expressed in high levels in both human heart and skeletal muscle tissues. To better understand how MAPKAP kinase 2 is regulated in myocardium, cultured rat cardiac myoblast (H9c2) cells were stimulated with heat shock, H2O2-induced oxidative stress, or phorbol ester (PMA). Enzymatic activity of cellular MAPKAP kinase 2 in the cell lysates was evaluated using an in vitro kinase assay. Exposure of H9c2 cells to heat shock or oxidative stress induced a transient increase of cellular MAPKAP kinase 2 activity, which reached its peak level within 5 min. In contrast, stimulation of H9c2 cells with PMA, a potential myocardial hypertrophic factor, induced a sustained increase of cellular MAPKAP kinase 2 activity that was detectable for over 1 h. In addition, in vitro protein phosphorylation analysis with recombinant MAPKAP kinase 2 showed that small heat shock protein (hsp25) served as a major substrate molecule for the kinase in H9c2 cells and the protein phosphorylation of cellular hsp25 was stimulated by H2O2-induced oxidative stress or PMA treatment in intact H9c2 cells. Moreover, exposure of H9c2 cells to H2O2-induced oxidative stress or PMA rapidly activated cellular p38 MAP kinase as detected by the induced protein phosphorylation of the kinase. Taken together, these results strongly suggest that MAPKAP kinase 2 may be involved in stress-activated signal transduction in myocardium.
J Mol Cell Cardiol 1997 Aug
PMID:High expression and activation of MAP kinase-activated protein kinase 2 in cardiac muscle cells. 928 47

When a heart responds to increased workload it does so by hypertrophy. This is characterized by an increase in cell size in the absence of cell division, and is accompanied by distinct qualitative and quantitative changes in gene expression. The use of cardiomyocytes in cell culture has identified, besides mechanical loading, a range of substances, such as cytokines, growth factors, catecholamines, vasoactive peptides and hormones, involved in mediating cardiac myocyte hypertrophy, and has enabled the molecular dissection of the pathways involved in signal transduction. Many different pathways are activated in response to different hypertrophic stimuli, and a growing number of crosslinks are being characterized between these pathways. Recent evidence suggests a central role for Ras in transmitting signals from G-protein coupled receptors, from growth factor receptors and from cytokine receptors not only down the Raf-MEK-ERK pathway to the nucleus, but also to various other cytosolic effectors. The evaluation of distinct morphological phenotypes, together with biochemical data on gene regulation, suggests that interactions between different signaling pathways take place. Each stimulus provokes a typical cellular phenotype and different stimuli may act alone or in concert in a synergistic, antagonistic or permissive manner. Consequently, hypertrophy of cultured cardiomyocytes cannot simply be characterized as the reversal to the fetal gene expression program. Thus, hypertrophic growth of the heart may similarly be the result of a complex combinatorial action of various stimuli, which may also lead to different morphological and biochemical phenotypes with distinct physiological properties.
J Mol Cell Cardiol 1997 Nov
PMID:Signaling pathways in cardiac myocyte hypertrophy. 940 63

This study was designed to assess whether the protective effect of ischemic preconditioning can be adapted for myocardium undergoing 6 h of no-flow ischemia. Twelve isolated rat hearts were either perfused with oxygen-bicarbonated Krebs-Henseleit buffer in the Langendorff mode for 35 min (n=6), or perfused in the same way for 20 min, following 5 min of global normothermic ischemia and 100 min of buffer-perfusion (n=6). The 12 hearts were then preserved for 6 h in HTK solution at 4 degrees C, followed by 30 min of reperfusion. Recovery of cardiac function, metabolic activity and intracellular free calcium concentration were compared between the two groups. After 6 h ischemia, the hearts that underwent preconditioning showed better recovery of left ventricular developed pressure (P<0.01), a lower end-diastolic pressure level (P<0.05), less creatine kinase leakage and a lower calcium concentration. There was no statistical difference in the recovery rate of coronary flow and leakage rate of LDH between the two groups. In conclusion, this experiment demonstrates that ischemic preconditioning improved myocardial functional recovery after 6 h of hypothermic ischemic preservation in the isolated rat heart. Preconditioning might be a potential mechanism for preserving the heart against long-term ischemia/reperfusion injury.
Int J Cardiol 1997 Dec 01
PMID:Cardioprotective efficacy of ischemic preconditioning on long-term myocardial ischemia. 946 84

The hypertrophic response is characterized by increased myofibril/sarcomere organization, induction of the cardiac specific atrial natriuretic factor (ANF) and myosin light chain-2 (MLC-2v) genes, and an increase in total cell volume. The alpha1-adrenergic agonist phenylephrine induces both the morphological and biochemical markers of hypertrophy in cultured neonatal rat ventricular cardiomyocytes. Previous studies have suggested a functional requirement for the heterotrimeric G-protein, Galphaq, for a subset of the hypertrophic phenotypes. The small GTPases Ras and Rho have also been implicated in phenylephrine-induced hypertrophy. To further delineate the role of Galphaq in hypertrophy, a constitutively active mutant of Galphaq was transiently transfected in primary rat ventricular cardiomyocytes. This molecule was sufficient to induce ANF-, AP1-, and MLC-2-driven gene expression. Co-transfection of Galphaq and dominant negative Ras or dominant negative Raf resulted in dose-dependent inhibition of ANF-driven expression. Both dominant negative Rho, and the Rho inhibitor C3-transferase, also attenuated Galphaq- and Ras-induced ANF-driven gene expression. Cells transfected with active Galphaq did not show a detectable increase in activation of the mitogen activated protein kinases ERK or SAPK. However, activity of the MAP-kinases appears to be important for Galphaq-induced gene expression since the MAP-kinase phosphatase Clone 100 and catalytically inactive SAPK strongly inhibited Galphaq-induced ANF expression. Thus, our studies indicate Galphaq-induced hypertrophic gene expression requires the small G-proteins Ras and Rho. The data also indicates that Galphaq mediated gene expression is dependent on functional MAP-kinases and that multiple signaling pathways contribute to Galphaq-mediated cardiac cell hypertrophy.
J Mol Cell Cardiol 1998 Mar
PMID:Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytes. 951 26

We previously reported that transforming growth factor-beta1 (TGF-beta1) potentiated alpha1-adrenergic and stretch-induced c-fos mRNA expression and norepinephrine (NE)-induced amino acid incorporation in rat cultured myocardial cells (MCs). In the present study, we attempted to explore the mode of TGF-beta1 action for c-fos gene expression in MCs. In the transient transfection assay, TGF-beta1 potentiated NE- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated c-fos promoter/enhancer, but not forskolin-activated c-fos promoter/enhancer. The c-fos serum response element (SRE) and the TPA response element (TRE) were responsible for TGF-beta1-induced potentiation of the NE or TPA action. Although TGF-beta1 activated not only the wild-type c-fos SRE, but also the mutated c-fos SRE, which contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, TPA activated the wild-type c-fos SRE but not the mutated c-fos SRE. TGF-beta1 did not potentiate the effects of TPA on the activation of mitogen-activated protein kinase (MAPK) and the phosphorylation of Elk-1 and SAP-1a, which belong to TCF at the c-fos SRE. These results indicate that TGF-betaf potentiates the c-fos SRE activated by PKC through the SRF binding site. TGF-beta1 is involved in the regulation of c-fos gene expression through the c-fos SRE and is subsequently involved in the regulation of the gene which has the TRE in the promoter/enhancer region.
J Mol Cell Cardiol 1998 Mar
PMID:Transforming growth factor-beta1 and protein kinase C synergistically activate the c-fos serum response element in myocardial cells. 951 31


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