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:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There were few reports demonstrating behavior of kinin and kininogen in the nephrotic syndrome. In this paper, coagulation factors related to contact activation, such as factor XII (FXII), factor XI (FXI), prekallikrein (PK), high molecular weight kininogen (HMWKG), and kinins were measured in 15 cases of nephrotic syndrome, and clinical significance of these results were discussed. Plasma FXII activity was markedly decreased in the onset and florid stages of nephrotic syndrome, and this decrease was not correlated with plasma albumin level, which suggested marked activation of this factor in these stages. However, the decrease of PK was slight at the above stages. Activations of contact factors were not parallely occurred with the marked consumption of FXII. Plasma kinin activity was not increased in the onset and critical stages of the nephrotic syndrome but increased in the convalescent and chronic stages, while HMWK level was maintained higher than normal throughout the course. Plasma angiotensin-converting enzyme (kininase II) activity was increased in the early stage and decreased lower than normal during the course of the disease. It was concluded that kinin formation in the nephrotic syndrome was not due to the activation of intrinsic coagulation system but due to release of kinin from low molecular weight kininogen. This increased level of kinin activity in convalescent and chronic stage may be related to the healing process during the course of this syndrome. Low kinin activity in the early stage of this disease might be also explained by increased kininase II activity.
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PMID:Mechanism and significance of kinin formation in nephrotic syndrome. 302 75

Bradykinin, the end product of activation of the plasma contact system, may play a significant role in reactions to contrast material and in other forms of anaphylactoid and anaphylactic responses to drugs or antigens. Activation of factor XII initiates activity in the plasma contact system, and we have identified factors (negatively charged surfaces) present in elevated concentrations in the plasma of patients who are asthmatic or allergic that can "prime" their plasma for the initiation and/or potentiation of factor XII activation. In other studies, we have shown that persons who react to contrast material and persons who are asthmatic or allergic share both a potential for accelerated contact system activity and evidence of an increased mean concentration of low-level contact system products. Recently, we have found that contrast media can inhibit angiotensin-converting enzyme, the substance that hydrolyzes bradykinin and limits its systemic effects. Thus, a number of factors suggest that it is the potential for increased production of bradykinin in persons who are allergic or asthmatic that may account for the greatly increased susceptibility of these patients to contrast material. This susceptibility may be critically triggered by the contrast media-induced inhibition of angiotensin converting enzyme. In view of these findings, the possibility exists that most, if not all, significant reactions to contrast material require an underlying allergic diathesis that may, or may not, be apparent by history and conventional diagnostic testing.
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PMID:A coherent biochemical basis for increased reactivity to contrast material in allergic patients: a novel concept. 350 Jun 22

The active fragment derived from factor XII (factor XIIf) was purified from human plasma and administered intravenously to normotensive conscious rats. Factor XIIf-mediated hypotension was dose-dependent and augmented by pretreatment with captopril, an inhibitor of the bradykinin-processing enzyme kininase II. These results therefore suggest that factor XIIf-mediated hypotension is due to the formation of bradykinin.
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PMID:Hypotensive effect of human factor XII active fragment in conscious normotensive rats: role of bradykinin. 640 Mar 78

Taken together, with the wide-spread use of ACE-inhibitors within the dialysis population, a novel type of hypersensitivity reaction has been recognized, which may occur not only during hemodialysis but also during other forms of extracorporeal therapy. From the data available today, it seems that such reactions are triggered by negatively charged biomaterials which are capable to activate factor XII, leading among others to the generation of bradykinin. Normally this kinin is rapidly degraded by the serine proteinase kininase II. Thus, in the absence of ACE inhibitors plasma bradykinin levels increase only moderately during dialysis with AN69 membranes and clinically most patients are free of symptoms. However, once kininase II, which is identical with converting enzyme, is blocked by ACE inhibitors, plasma levels may increase more than 100-fold and patients will suffer from severe anaphylaxis. Based on our present knowledge, the consequences for clinical medicine are straightforward. It is mandatory to avoid the combination of negatively charged membranes or other biomaterials with ACE inhibitor therapy. As there are many different membranes available, this should be no unsurmountable problem in the setting of clinical hemodialysis.
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PMID:Anaphylactoid reactions during hemodialysis. 792 83

Recent studies indicate that assembly of high molecular weight kininogen on its multiprotein receptor allows for prekallikrein activation. On endothelial cells, factor XII activation is secondary to prekallikrein activation and amplifies it. The immediate consequence of plasma prekallikrein activation is the cleavage of high molecular weight kininogen (HK) with liberation of bradykinin. Cleaved high molecular weight kininogen is antiangiogenic. Bradykinin stimulates tPA liberation and nitric oxide formation. In addition, formed plasma kallikrein promotes single-chain urokinase activation and subsequent plasminogen activation. Kininogens and their breakdown products also are antithrombins. The angiotensin converting enzyme breakdown product of bradykinin prevents canine coronary thrombosis. The author presents a new hypothesis for physiologic assembly and activation of the plasma kallikrein/kinin system and discusses its influence on vascular biology.
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PMID:Plasma kallikrein/kinin system: a revised hypothesis for its activation and its physiologic contributions. 1096 74

Proteins of the plasma kinin-forming cascade bind to endothelial cells and activation of the cascade can be initiated along the surface. The light chain of high molecular weight kininogen (HK) (domain 5) and factor XII bind to gC1qR, the heavy chain of HK (domain 3) binds to cytokeratin 1 and the interactions are zinc dependent. Prekallikrein binds to domain 6 of HK. Antisera to gC1qR and cytokeratin 1 inhibit binding and activation. Incubation of normal plasma with endothelial cells leads to gradual conversion of prekallikrein to kallikrein, while plasma deficient in factor XII or HK are inactive within a 2-hour time frame. Thus factor XII is critical for activation to proceed. Augmentation of these reactions may occur when C1 inhibitor is functionally deficient or with ACE inhibitors which also inhibit kininases.
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PMID:Activation of the plasma kinin forming cascade along cell surfaces. 1130 9

Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as the angioedema seen with ACE inhibitors and may contribute to bronchial hyperreactivity in asthma. Formation of bradykinin occurs in the fluid phase and along cell surfaces requiring interaction of factor XII, prekallikrein, and high M(r) kininogen (HK). Recent data suggest that activation of the kinin-forming cascade can occur on the surface of endothelial cells, even in the absence of factor XII. We sought to further define this factor XII-independent mechanism of kinin formation. Both cytosolic and membrane fractions from endothelial cells possessed the ability to catalyze prekallikrein conversion to kallikrein, and activation depended on the presence of HK and zinc ion. We fractionated the cytosol by ion exchange chromatography and affinity chromatography by using corn trypsin inhibitor as ligand. The fractions with peak activity were subjected to SDS gel electrophoresis and ligand blot with biotinylated corn trypsin inhibitor, and positive bands were sequenced. Heat shock protein 90 (Hsp90) was identified as the protein responsible for zinc-dependent prekallikrein activation in the presence of HK. Zinc-dependent activation of the prekallikrein-HK complex also depended on addition of either alpha and beta isoforms of Hsp90 and the activation on endothelial cells was inhibited on addition of polyclonal Ab to Hsp90 in a dose-dependent manner. Although the mechanism by which Hsp90 activates the kinin-forming cascade is not understood, this protein represents the cellular contribution to the reaction and may become the dominant mechanism in pathologic circumstances in which Hsp90 is highly expressed or secreted.
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PMID:Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. 1179 53

The plasma kinin-forming cascade can be activated by contact with negatively charged macromolecules leading to binding and autoactivation of factor XII, activation of prekallikrein to kallikrein by factor XIIa, and cleavage of high molecular weight kininogen (HK) by kallikrein to release the vasoactive peptide bradykinin. Once kallikrein formation begins, there is rapid cleavage of unactivated factor XII to factor XIIa, and this positive feedback is favored kinetically over factor XII autoactivation. Examples of surface initiators that can function in this fashion are endotoxin, sulfated mucopolysaccharides, and aggregated Abeta protein. Physiological activation appears to occur along the surface of endothelial cells both by the aforementioned contact-initiated reactions as well as bypass pathways that are independent of factor XII. Factor XII binds primarily to cell surface u-PAR (urokinase plasminogen activator receptor); HK binds to gC1qR via its light chain (domain 5) and to cytokeratin 1 by its heavy chain (domain 3) and, to a lesser degree, by its light chain. Prekallikrein circulates bound to HK (as does coagulation factor XI), and prekallikrein is thereby brought to the surface as HK binds. All cell-binding reactions are dependent on zinc ion. Endothelial cells (HUVECs) have bimolecular complexes of u-PAR-cytokeratin 1 and gC1qR-cytokeratin 1 at the cell surface plus free gC1qR, which is present in substantial molar excess. Factor XII appears to interact primarily with the u-PAR-cytokeratin 1 complex, whereas HK binds primarily to the gC1qR-cytokeratin 1 complex and to free gC1qR. Release of endothelial cell heat shock protein 90 (Hsp90) or the enzyme prolylcarboxypeptidase leads to activation of the bradykinin-forming cascade by activating the prekallikrein-HK complex. In contrast to factor XIIa, neither will activate prekallikrein in the absence of HK, both reactions require zinc ion, and the stoichiometry suggests interaction of one molecule of Hsp90 (for example) with one molecule of prekallikrein-HK complex. The presence of factor XII, however, leads to a marked augmentation in reaction rate via the kallikrein feedback as well as to a change to classic enzyme-substrate kinetics. The circumstances in which activation is initiated by factor XII autoactivation or by these factor XII bypasses are yet to be defined. The pathologic conditions in which bradykinin generation appears important include hereditary and acquired C1 inhibitor deficiency, cough and angioedema due to ACE inhibitors, endotoxin shock, with contributions to conditions as diverse as Alzheimer's disease, stroke, control of blood pressure, and allergic diseases.
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PMID:Formation of bradykinin: a major contributor to the innate inflammatory response. 1570 22

HFR is an integrated hemodiafiltration system that utilizes a double chamber filter to separate convection from diffusion. The ultrafiltrate is regenerated by passage through a sorbent cartridge made up of resin and activated carbon. A small percentage of patients using this technique had gastrointestinal symptoms that included nausea/vomiting, diarrhea and/or stomach cramps approximately 1-2 hours after the start of HFR. We undertook a series of investigations to try and elucidate the cause of these reactions. Since the majority of the patients were taking ACE inhibitors, attention was focused on contact phase activation. Healthy and uremic plasma were incubated with different components of the HFR circuit. The activated carbon caused a moderate activation of factor XII and production of kallikrein, while there was no activation for the lines, double filter or resin. Patients taking ACE inhibitors may be at risk for treatments involved with contact phase activation as ACE inhibitors also block the degradation of bradykinin. A new sorbent cartridge has now been developed that contains only resin.
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PMID:[Contact phase activation can occur with certain types of activated carbon]. 1574 7

The combination of negatively-charged membranes and angiotensin I-converting enzyme inhibitors (ACEi) evokes hypersensitivity reactions (HSR) during hemodialysis and bradykinin (BK)-related peptides have been hypothesized as being responsible for these complications. In this study, we tested the effects of neutralizing the membrane electronegativity (zeta potential) of polyacrylonitrile AN69 membranes by coating a polyethyleneimine layer (AN69-ST membranes) over the generation of kinins induced by blood contact with synthetic membranes. We used minidialyzers with AN69 or AN69-ST membranes in an ex vivo model of plasma and we showed that plasma dialysis with AN69 membranes led to significant BK and des-Arg(9)-BK release, which was potentiated by ACEi. This kinin formation was dramatically decreased by AN69-ST membranes, even in the presence of an ACEi, and kinin recovery in the dialysates was also significantly lower with these membranes. High molecular weight kininogen and factor XII detection by immunoblotting of the protein layer coating both membranes corroborated the results: binding of these proteins and contact system activation on AN69-ST membranes were reduced. This ex vivo experimental model applied to the plasma, dialysate and dialysis membrane could be used for the characterization of the kinin-forming capacity of any biomaterial potentially used in vivo in combination with drugs which modulate the pharmacological activity of kinins.
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PMID:The effect of electronegativity and angiotensin-converting enzyme inhibition on the kinin-forming capacity of polyacrylonitrile dialysis membranes. 1807 88


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