Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The influence of the renin-angiotensin system on the control of cell communication was investigated in isolated ventricular cell pairs of adult rats. It was found that angiotensin II (1 microgram/ml) reduced the junctional conductance (gj) by about 55% within 20 s. This effect of angiotensin II was suppressed by DuP 753--an angiotensin receptor blocking agent. Enalapril (1 microgram/ml)--an angiotensin converting enzyme inhibitor--caused an increase in junctional conductance (106%) within 2 min. The effect of enalapril on gj was not related to activation of beta-adrenergic receptors or cAMP-dependent protein kinase. The effect of angiotensin II on gj was suppressed by staurosporine--a potent inhibitor of protein kinase C. This finding indicates that the peptide is changing gj through activation of protein kinase C. The increase in cell coupling caused by enalapril raises the possibility that the antiarrhythmic action of enalapril as well its effect in congestive heart failure are related to an increase in electrical synchronization of cardiac myocytes.
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PMID:The role of the renin-angiotensin system in the control of cell communication in the heart: effects of enalapril and angiotensin II. 128 Jul 22

The peptide hormone angiotensin-II (AII) is a potent vasoconstrictor and major regulator of aldosterone synthesis. In addition, AII also has growth-promoting effects. We have recently shown that the lipoxygenase (LO) pathway of arachidonic acid plays a major role in AII-induced aldosterone synthesis in adrenal glomerulosa cells. The LO pathway is also involved in the vasopressor and renin-inhibitory effects of AII. However, the role of LO products in AII-induced mitogenic effects have not yet been investigated. In the present studies we have evaluated the role of the LO pathway in AII-induced proliferative responses in a bovine adrenocortical cell clone termed AC1 cells. In addition, the potential receptor type and mechanism of AII-induced proliferation was studied by evaluating the effect of specific nonpeptide type 1 and type 2 AII receptor antagonists and the role of protein kinase-C (PKC). AII-induced DNA synthesis was significantly attenuated by two structurally dissimilar LO inhibitors, baicalein and phenidone. In addition, the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) itself caused a significant increase in DNA synthesis, suggesting that the 12-LO pathway in part plays a role in AII-mediated mitogenesis. AII-induced proliferative responses were blocked by the type 1 AII receptor antagonist. Both AII- and 12-HETE-induced increases in DNA synthesis were markedly inhibited by two PKC blockers, staurosporine and sangivamycin. Further, both AII and 12-HETE could activate PKC by translocating it from the cytosol to the membrane fraction, as determined by Western immunoblotting. These results suggest that both 12-LO activation and protein kinase-C have an important role in AII-induced adrenal cell proliferation.
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PMID:Mechanism of angiotensin II-induced proliferation in bovine adrenocortical cells. 150 59

The effect of enalapril and angiotensin II on junctional conductance (gj) of isolated rat heart cell pairs was investigated. It was found that enalapril (1 micrograms/ml) increases gj by 106 +/- 3.1% (SEM) (n = 20) within 4 min. The effect of enalapril on gj was not suppressed by propranolol (10(-6) M) or by a cAMP-dependent protein kinase inhibitor. Angiotensin II (1 micrograms/ml) reduced gj by 55%. These observations might indicate that an intrinsic renin-angiotensin system in heart is involved in the control of gj in cardiac muscle.
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PMID:Enalapril, an inhibitor of angiotensin converting enzyme, increases the junctional conductance in isolated heart cell pairs. 172 43

This article describes investigations of several aspects of the molecular biology of the human renin gene and the three-dimensional structure of renin and its precursor, prorenin. Because of the importance of the RAS in hypertension, heart failure, renal failure, and possibly other disorders such as atherosclerosis, it is critical to understand the detailed control of this system. This control involves regulation at the transcriptional level, folding of prorenin, sorting of prorenin to a regulated pathway where it is proteolytically cleaved to renin and released in response to secretogogues, constitutive release of uncleaved prorenin, and nonproteolytic activation of prorenin. Currently there is great interest not only in the control of renin in the kidney, the sole source of circulating renin, but also at extrarenal sites where RAS activity may regulate cardiovascular functions. The renin gene was found to be expressed significantly in the renal juxtaglomerular cells and several other cell types. Most tissue culture cells did not express the gene; exceptions were cultured SK-LMS-1 cells and cAMP-stimulated human lung fibroblasts. Cultured human uterine-placental cells expressed the human renin gene at levels higher than in other cell types assessed. Renin mRNA had the same start site in the placental cells as the kidney and was regulated by calcium ionophores and cAMP. Thus, these cells provide primary nontransformed human cells to study the homologous human promoter. Transfected renin promoters showed cell type-specific expression and cAMP responsiveness in these cells in constructs containing as few as 102 bp of 5'-flanking DNA. DNA upstream from this appears to contain an inhibitory element(s) that may have some tissue specificity in its distribution. The cAMP response is not due to cAMP induction of a transcription factor that secondarily affects the renin promoter. A novel element may be involved, since the promoter does not contain a CRE element that mediates many cAMP responses, and the cells do not appear to respond to another known cAMP-responsive transcription factor, AP-2. Studies with transfected vectors expressing a mutant cAMP-responsive protein kinase A regulatory subunit suggest that cAMP is not responsible for basal renin promoter activity in the placental cells. By contrast, cAMP induces in essence gene activation in WI26VA4 transformed human lung fibroblasts in which renin mRNA levels increase by up to 150-fold in response to forskolin. Thus, cAMP may activate renin gene expression under certain circumstances and tissue-specific renin gene expression may be directed by more than one mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular biology of human renin and its gene. 174 21

Three classes of vasodilators mediate their effects through the activation of guanylate cyclase and the increased synthesis of cyclic GMP. Nitrovasodilators such as nitroglycerin, nitroprusside, hydroxylamine, azide, etc. result in the generation of the nitric oxide free radical that activates the cytosolic (soluble) isoenzyme form of guanylate cyclase. These agents have been useful in increasing cyclic GMP synthesis in numerous model systems and these effects are independent of extracellular calcium. The increased synthesis of cyclic GMP and the activation of cyclic GMP-dependent protein kinase result in the altered phosphorylation of many smooth muscle proteins including the dephosphorylation of myosin light chain, which is associated with vascular and tracheal smooth muscle relaxation. These latter effects may result from cyclic GMP decreasing cytosolic free calcium concentrations and the activity of myosin light chain kinase. Another class of vasodilators, designated endothelium-dependent vasodilators, includes a long list of agents such acetylcholine, histamine, A23187, ATP, thrombin, etc. that relax vessels only when the endothelium is intact. These agents result in the increased endothelial synthesis and/or release of a factor(s) designated endothelial-derived relaxant factor (EDRF), the structure of which is unknown. This labile factor also activates the soluble isoenzyme form of guanylate cyclase in the smooth muscle resulting in cyclic GMP accumulation and the same cascade of events as above. There is evidence that even under basal, non-stimulated conditions there is EDRF release that influences vascular tone due to the increased synthesis of cyclic GMP. A third class of vasodilators, atrial natriuretic factor (ANF) or atriopeptins, includes a family of peptides that are produced in cardiac atria and other tissues and influence cardiovascular volume and dynamics by causing natriuresis, diuresis, vasodilation and decreased renin, aldosterone and vasopressin secretion. These peptide hormones also increase cyclic GMP synthesis in vascular, renal, adrenal and other tissues. These effects are mediated through specific ANF receptors that couple to and activate the membrane (particulate) isoenzyme form of guanylate cyclase and increase cyclic GMP-dependent protein kinase activity. There are two ANF receptor subtypes in most cells and tissues that are 130,000 and 66,000 daltons. The ANF receptor of about 130,000 daltons, designated receptor ANF-R1 copurifies with particulate guanylate cyclase through numerous procedures and may be part of the membrane-associated guanylate cyclase complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. 289 Jan 72

Vasopressin is actively involved in the regulation of blood pressure to the same degree as catecholamines and the renin angiotensin aldosterone system are, especially in stressful situations. Vasopressin induces and increase in blood pressure when mechanisms buffering its potent vasoconstrictor effect are altered. Vasopressin binds to specific membrane receptors classified into two main types. The V1 receptors found in blood vessels, platelets and hepatocytes are linked to two intra-cellular messengers, namely 1,2 diacylglycerol and 1,4,5 inositol triphosphate which stimulate protein kinase C and calcium-calmodulin kinase in the presence of calcium. V2-renal receptors stimulate the production of cyclic AMP which activates protein kinase A. Subsequently, the actin network is altered and particles containing pores agregate at the cell surface to produce water molecules reabsorption. Vasopressin modifies human hemostasis via platelet aggregation, stimulation of the three fractions of factor VIII, of factor XII and of fibrinopeptide A. These properties were used to treat hemostasis abnormalities seen in Von Willebrand's disease and hemophilia. There is a feed-back loop between vasopressin and the atrial natriuretic factor: vasopressin stimulates atrial natriuretic factor release via a V1 action whereas the atrial natriuretic factor reduces vasopressin release and inhibits vasopressin antidiuretic action.
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PMID:[Vasopressin, the antidiuretic hormone]. 295 73

Congestive heart failure is a complex physiopathological state where both myocardial hypo-contraction and excessive peripheral vasoconstriction lead to lower cardiac output. The increase in cytosolic calcium concentration triggers the contractile processus. Digitalis inhibits the Na+/K+ ATPase enzyme and indirectly increases intracellular calcium concentration. beta 1 agonists increase the synthesis of cAMP-dependent protein kinase and hence the recruitment of new receptor-operated calcium channels which increase the calcium influx and the mobilization from its intracellular storage sites. Vascular smooth muscle contraction occurs with calcium influx into the cell resulting from various receptor activation. In congestive heart failure, activation of the sympathetic nervous system and of the renin-angiotensin system leads to neurohumoral-induced peripheral vasoconstriction. Renal effects of angiotensin II and aldosterone are responsible for sodium and water retention. alpha 1-blocking agents are drugs that block competitively the catecholamines effects on vascular receptors. Angiotensin I-converting-enzyme inhibitors block the formation of the key-element of the system: angiotensin II. Both alpha 1-blocking agents and converting-enzyme inhibitors show vasodilatator effects and acutely improve hemodynamic status of patients with congestive heart failure. Converting-enzyme inhibitors exhibit specific improvement of intrarenal hemodynamics and do not induced sodium and water retention in longterm therapy.
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PMID:[Pharmacological bases of the treatment of cardiac insufficiency]. 303 68

Prorenin (Pro) is synthesized in a number of human utero-placental tissues, including chorion, decidua, villous placenta and probably mesenchymal cells. The release of Pro from these extra-renal tissues follows new protein synthesis and appears to utilize the constitutive secretory pathway. Unlike processing in the kidney, very little of the Pro is subsequently cleaved to the smaller product (active renin). Primary signals which regulate Pro include protein hormones and peptides (relaxin, endothelin, hCG), amines (epinephrine, norepinephrine, and related beta adrenergic agents), and eicosanoids. These agents increase the mRNA for prorenin at a time before peak secretory effects are noted. Other extracellular signals have negative regulatory effects. These include angiotensin, endotoxin and cytokines (TNF-alpha and interleukin-1 B). There is also evidence that glucocorticoid receptor activation has an inhibitory effects on Pro release in placenta. Second messengers involved in the regulation of Pro include cyclic AMP and protein kinase A (PKA), protein kinase C (PKC), and calcium. The possible biological effect(s) of the extracellular Pro are unknown but may be due to direct generation of angiotensin I. Since angiotensin-peptides have a number of trophic effect on both vascular and non-vascular tissues, regulation of utero-placental Pro by autocrine, paracrine or endocrine signalling may be critical in normal fetal and/or placental development.
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PMID:Regulation of utero-placental prorenin. 748 44

Several authors have shown that angiotensin II stimulates hepatic angiotensinogen synthesis in vivo, ex vivo and in vitro. In previous studies we have demonstrated that this effect of angiotensin II depends mainly on a transient inhibition of adenylyl cyclase and is the consequence of a stabilization of angiotensinogen mRNA. In the present study we describe the isolation of a polysomal 12 kDa protein which, in band shift and cross link assays, shows a specific affinity to the 3' untranslated region (3' UTR) of angiotensinogen mRNA and prevents enzymatic degradation of angiotensinogen mRNA in a cell-free incubation system. [32P]UTP-labelled or unlabelled 3' fragments of angiotensinogen mRNA were synthesized on a transcription vector (pGEM5zf+) into which the corresponding DNA sequence was cloned after restriction from vector pRAG 16. Binding of the 12 kDa protein to the radioactively labelled 3' UTR of angiotensinogen mRNA could be displaced by unlabelled 3' UTR mRNA fragments but not by a renin mRNA of comparable length derived from the coding region. The RNA-binding protein appears to be derived from a higher molecular mass precursor (45 kDa) which is preferentially present under reducing conditions in vitro; the active low molecular mass form is evident in the absence of reducing agents. In a cross link experiment we established that a band shift signal which was obtained in the presence of the 45 kDa protein preparation exclusively depends on RNA binding of the active 12 kDa protein. In addition, a phosphorylation step may be involved in the activation of the 12 kDa protein, since its molecular mass and isoelectric point correlate with proteins which were phosphorylated in response to transient decreases of cAMP (induced by guanfacine or angiotensin II) or in response to a direct inhibition of protein kinase A by the cAMP antagonist Rp-cAMP. The importance of phosphorylation reactions for the stabilization of angiotensinogen mRNA was further assessed in a cell-free incubation system of rat liver parenchymal cells. These studies demonstrated that in the presence of acid phosphatase (1 U/ml) the half-life of angiotensinogen was significantly decreased. In the same incubation system the 12 kDa protein increased the half-life of endogenous as well as of exogenous angiotensinogen mRNA three- to fourfold, while no stabilizing effect was apparent when exogenous angiotensinogen mRNA from which the 3' tail had been deleted was added.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Contribution of a 12 kDa protein to the angiotensin II-induced stabilization of angiotensinogen mRNA: interaction with the 3' untranslated mRNA. 761 10

It is known that mechanical stress directly changes the conformation of the functional proteins, or directly activates enzymes such as phospholipase in the plasma membrane. The integrin-cytoskeleton complex may be an alternative candidate structure for a mechanoreceptor and a transducer. The cytoskeleton has been also shown to play an important role in secretion. Mechanical stress may stimulate the secretion of some cytokines or angiotensin II, which may generate multiple intracellular signals as a secondary event. External stimuli are generally transduced into the nucleus through the activation of protein kinase cascade. Stretching of cardiac myocytes stimulates the activity of PKC, Raf-1 kinase, MAP kinase kinase. MAP kinase and S6 kinase. In cardiac myocytes, mechanical stress directly induces gene expression as well as protein synthesis. Immediate early genes are first induced, and then fetal-type genes are reinduced. Both in hypertrophied hearts and in the experimental model of cardiac hypertrophy induced by pressure overload. Ca(2+)-ATPase content of cardiac myocytes is depressed. Reduced function of sarcoplasmic reticulum causes insufficient decrease of intracellular calcium in diastole and induces slowing of ventricular relaxation. In the interstitium of pressure overloaded hearts, the accumulation of collagen fiber is increased. The abnormal deposit leads to increased chamber stiffness and diastolic dysfunction. Furthermore, TGF-beta and tissue renin-angiotensin system are up-regulated in pressure overloaded hearts, both of which accelerate the interstitial fibrosis.
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PMID:Interaction of cardiac myocytes and non-myocytes in mechanical stress-induced hypertrophy. 777 62


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