Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
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PMID:Mechanisms of action of nitrates. 787 67

Endothelin-1 is a peptide hormone constitutively secreted by vascular and endocardial endothelial cells. Secretion of endothelin-1 is increased under certain pathophysiological conditions, including coronary vasospasm, cardiac ischaemia and myocardial infarction. We have examined the effect of endothelin-1 on the protein kinase A (PKA)-dependent chloride current in voltage-clamped guinea pig ventricular myocytes. This conductance, induced by catecholamines through beta-adrenergic receptors, counteracts the simultaneously increased L-type calcium current by shortening the action potential duration. We report here that endothelin-1, acting through ETA (endothelin-1-selective) receptors, inhibited the current through a pertussis toxin-sensitive mechanism, analogous to muscarinic receptors, by reducing the intracellular cyclic AMP concentration. This effect of endothelin-1 should help protect the ventricle against potentially arrhythmogenic shortening of the action potential during ischaemia when the circulating levels of catecholamines are increased.
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PMID:Inhibition of the cardiac protein kinase A-dependent chloride conductance by endothelin-1. 751 70

Changes between serial laboratory test results can be significant, even if none of the individual results exceeds the reference interval. We developed a statistical method for the calculation of reference change limits from routine patients' data for situations in which the majority of the patients can be considered suitable reference subjects. The method was applied to cardiac enzyme data [creatine kinase (CK; EC 2.7.3.2), creatine kinase isoenzyme MB (CK-2), lactate dehydrogenase (LD; EC 1.1.1.28), and lactate dehydrogenase isoenzyme 1 (LD-1)] from 2029 consecutive patients. We used hospital discharge diagnoses to exclude patients with the diagnosis of myocardial infarction or myocarditis, but we also studied the characteristics of the method on unselected patients' data. The reference change limits derived from the diagnosis-selected patient group were as follows (U/L, activity measurements in serum at 37 degrees C according to Scandinavian recommendations): CK from -39 to 27, CK-2 from -8 to 7, LD from -86 to 85, and LD-1 from -19 to 15. Similar limits were obtained by conventional statistical methods from a group of 29 hospitalized patients with no myocardial symptoms. Our results suggest that it is possible to produce clinically applicable reference change limits from routine data.
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PMID:Method for determining reference changes from patients' serial data: example of cardiac enzymes. 822 24

The polymorphonuclear granulocyte, or neutrophil, has been implicated as a mediator of tissue-destructive events because it releases the preformed proteolytic enzymes elastase and cathepsin G, and, as a result of myeloperoxidase action, hypochlorous acid. We show that elastase inactivates and fragments creatine kinase isoenzymes CK-2 and CK-3, and, to a lesser extent, lactate dehydrogenase (LD) isoenzyme LD-1, whereas cathepsin G acts only on CK-2. Both neutrophil enzymes act on LD-3. The course of inactivation was followed by measuring the loss of catalytic activity at 37 degrees C. The evidence for fragmentation was obtained by gel filtration; electrophoresis after sample treatment with sodium dodecyl sulfate and 2-mercaptoethanol was less satisfactory for this purpose. Hypochlorous acid inactivates CK activity by about 75% at concentrations as low as 8 mumol/L and totally at concentrations > 140 mumol/L, whereas LD activity is not affected until concentrations exceed 200 mumol/L. After a myocardial infarction, the number of neutrophils increases; they are triggered and concentrate around damaged myocardial tissue. Our data suggest that neutrophils may inactivate and fragment "cardiac" enzymes released from such damaged tissue.
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PMID:In vitro effect of elastase and cathepsin G from human neutrophils on creatine kinase and lactate dehydrogenase isoenzymes. 828 31

The diagnostic efficacy of creatine kinase (CK) isoforms (CK-3 and CK-2) was compared with measurement of CK-2 mass concentrations for the early diagnosis of myocardial infarction (MI). Serial serum samples drawn from 76 patients with confirmed MI and 55 non-MI patients were used for determining CK-2 mass concentrations and the MM3/MM1 (CK-3 isoforms) and MB2/MB1 (CK-2 isoforms) ratios. We compared the diagnostic utility of each by receiver-operating-characteristic (ROC) curve and likelihood ratio analyses. Our results indicate that all three tests were ineffective within the first 4 h after the onset of chest pain. All three were most effective at 4-18 h after onset, but both CK-3 and CK-2 isoform ratios were less effective than CK-2 mass concentrations in the next 6-h period (18-24 h). In the critical time between 3 and 6 h, the diagnostic performance of all three was comparable.
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PMID:Diagnostic evaluation of creatine kinase-2 mass and creatine kinase-3 and -2 isoform ratios in early diagnosis of acute myocardial infarction. 844 62

Myocytes isolated from rat hearts that have suffered 35% myocardial infarction (MI) 3 wk prior have lower peak cytosolic Ca2+ concentration ([Ca2+]i) during contraction compared with Sham myocytes, a difference that is amplified by isoproterenol or high extracellular Ca2+ concentration ([Ca2+]o). To evaluate whether reduced [Ca2+]i in MI myocytes is due to decreased Ca2+ entry, we measured [3H]PN-200-110 [dihydropyridine (DHP)] binding and whole cell Ca2+ current (ICa). DHP binding decreased in both sarcolemmal vesicles and intact myocytes from hearts 3 wk after MI. In contrast, ICa was not different between Sham and MI myocytes incubated at 1.8 mM [Ca2+]o. At 5.0 mM [Ca2+]o, ICa increased similarly in Sham and MI myocytes. Steady-state voltage dependence of activation and inactivation were similar between Sham and MI myocytes, as were the fast- and slow-inactivation time constants. Isoproterenol (1 microM) significantly increased ICa in Sham but not in MI myocytes. Forskolin (10 microM) dibutyryl adenosine 3',5'-cyclic monophosphate (5 mM) significantly increased ICa in MI myocytes; the magnitude of ICa increase was similar to that observed in Sham myocytes. We conclude that 1) decreased systolic [Ca2+]i in MI myocytes was not due to reduced Ca2+ entry via L-type Ca2+ channels; 2) discrepancy between DHP binding (decrease) and ICa (no change) results may be explained by higher channel availability and/or increased long-opening modes (mode 2) in MI myocytes; 3) reduction in isoproterenol-induced [Ca2+]i increase in MI myocytes was partly due to decreased ICa, resulting in less Ca2+ release from sarcoplasmic reticulum; 4) the adenylate cyclase-protein kinase A signal-transduction pathway functioned normally in MI myocytes; and 5) decreased beta-adrenergic responsiveness in MI myocytes was likely due to altered coupling by G proteins.
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PMID:Calcium currents in postinfarction rat cardiac myocytes. 857 75

The role of cyclic AMP-dependent protein kinase (PKA) and systolic function during the development of left ventricular hypertrophy (LVH) still remain uncertain. The aim of this work is to study PkA activity and mechanical heart function in two experimental heart hypertrophy models: specifically, one induced by pressure overload (Goldblatt model: two kidneys, one clamped, Gb); and another secondary to myocardial infarction (MI) generated by ligation of the left coronary artery. Hypertension in the Gb group becomes evident by the third and fourth week after surgery without any significant change in the corresponding sham group. The myocardial infarction group did not show any change in systolic pressure. Different degrees of LVH for the two experimental models were observed. Relative cardiac mass (RCM) and relative ventricular mass (RVM) increased 23 and 16%, respectively, above the sham-operated rats in MI group (P < 0.05). For the pressure overload model, the increase values were 42 and 44%, respectively (P < 0.05). Left ventricular hypertrophy was also evaluated through quantitative changes in cardiac beta-myosin heavy chain which agreed with morphometric studies in Goldblatt rats. Ventricular PKA activity did not show any significant difference with respect to the sham-operated group after induction of pressure overload. For the MI model, ventricular PKA activity changed only at day 7 post-infarction with a 289% increase above the sham-operated group (P < 0.05). The absence of activation of ventricular PKA after constriction of renal artery or myocardial infarction was also corroborated by the patterns of PKA-dependent phosphorylated proteins. While force-generating capacity was increased, there was no change in ventricular PKA activity, indicating that there is no relation between this enzyme and systolic stress-strain regression lines in either pressure overload or myocardial infarction conditions. Cyclic AMP-dependent protein kinase activity had no relation with development of cardiac hypertrophy in the two experimental models of LVH. These findings contribute to the hypothesis for a multifactorial interaction of different intracellular biochemical and molecular mechanisms in the genesis of cardiac hypertrophy.
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PMID:Cyclic AMP-dependent protein kinase and mechanical heart function in ventricular hypertrophy induced by pressure overload or secondary to myocardial infarction. 876 44

Hypoxia and reoxygenation are principal components of myocardial ischemia and reperfusion and have distinctive effects on the tissue. Both conditions have been associated with inflammation, necrosis, apoptosis, and myocardial infarction. Using a cell culture model of ischemia and reperfusion in which cardiac myocytes were exposed to cycles of hypoxia and reoxygenation, we report here that reoxygenation, but not hypoxia alone, caused sustained approximately 10-fold increases in phosphorylation of the amino-terminal domain of the c-jun transcription factor. The activation was similar to treatments with anisomycin or okadaic acid and correlated with the hypoxia-mediated depression of intracellular glutathione. Reoxygenation-induced c-Jun kinase activity was reduced by preincubating myocytes during the hypoxia phase with the spin-trap agent alpha-phenyl N-tert-butylnitrone or with N-acetylcysteine. The kinase activation was also inhibited by the tyrosine kinase inhibitor genistein but not by other protein kinase inhibitors. These results implicate unquenched reactive oxygen intermediates as the stimulus that initiates a kinase pathway involving the stress-activated protein kinases (JNKs/SAPKs) in reoxygenated cardiac myocytes.
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PMID:Hypoxia/reoxygenation stimulates Jun kinase activity through redox signaling in cardiac myocytes. 904 53

The ability of the cardiac myocyte to divide ceases shortly after birth. Thus, following severe injury, e.g., during myocardial infarction, the mature heart is unable to regenerate new tissue to replace the dead or damaged tissue. The identification of the molecules controlling the cessation of myocyte cell division may lead to therapeutic strategies which aim to re-populate the damaged myocardial area. Hence, we have determined the cell cycle profile, expressions and activities of the cyclin-dependent kinase inhibitors (CDKIs), p21CIP1 and p27KIP1, during rat ventricular myocyte development. Fluorescent activated cell sorting (FACS) analyses showed the percentage of S phase myocytes to be decreased significantly throughout development, concomitant with a significant increase in the percentage of G0/G1 and G2/M phase cells. The expression of p21CIP1 and p27KIP1 increased significantly throughout cardiac development and complexed differentially with a number of cyclins and CDKs. Furthermore, an adult myocyte extract reduced neonatal myocyte CDK2 kinase activity significantly (>30%, p<0.05) whereas immunodepletion of p21CIP1 from adult lysates restored CDK2 kinase activity. Thus, p21CIP1 and p27KIP1 may be important for the withdrawal of cardiac myocytes from the cell cycle and for maintaining the G0/G1 and G2/M phase blockades.
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PMID:Cell cycle profiles and expressions of p21CIP1 AND P27KIP1 during myocyte development. 989 46

Three weeks after myocardial infarction (MI) in the rat, remodeled hypertrophy of noninfarcted myocardium is at its maximum and the heart is in a compensated stage with no evidence of heart failure. Our hemodynamic measurements at this stage showed a slight but insignificant decrease of +dP/dt but a significantly higher left ventricular end-diastolic pressure. To investigate the basis of the diastolic dysfunction, we explored possible defects in the beta-adrenergic receptor-G(s/i) protein-adenylyl cyclase-cAMP-protein kinase A-phosphatase pathway, as well as molecular or functional alterations of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban (PLB). We found no significant difference in both mRNA and protein levels of sarcoplasmic reticulum Ca(2+)-ATPase and PLB in post-MI left ventricle compared with control. However, the basal levels of both the protein kinase A-phosphorylated site (Ser16) of PLB (p16-PLB) and the calcium/calmodulin-dependent protein kinase-phosphorylated site (Thr17) of PLB (p17-PLB) were decreased by 76% and 51% in post-MI myocytes (P<0.05), respectively. No change was found in the beta-adrenoceptor density, G(salpha) protein level, or adenylyl cyclase activity. Inhibition of phosphodiesterase and G(i) protein by Ro-20-1724 and pertussis toxin, respectively, did not correct the decreased p16-PLB or p17-PLB levels. Stimulation of beta-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB in post-MI myocytes to the same levels as in sham myocytes, suggesting that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a decrease in the generation of p16-PLB or p17-PLB. We found that type 1 phosphatase activity was increased by 32% (P<0.05) with no change in phosphatase 2A activity. Okadaic acid, a protein phosphatase inhibitor, significantly increased p16-PLB and p17-PLB levels in post-MI myocytes and partially corrected the prolonged relaxation of the [Ca(2+)](i) transient. In summary, prolonged relaxation of post-MI remodeled myocardium could be explained, in part, by altered basal levels of p16-PLB and p17-PLB caused by increased protein phosphatase 1 activity.
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PMID:Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases. 1053 53


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