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)

Peptide hormones are involved in the paracrine regulation of several physiological processes. A possible function of the kallikrein-kinin system (KKS) in mammalian reproduction has been discussed. To evaluate its putative role in spermatogenesis, we searched for components of the KKS (kallikrein, kininases, kinin receptor) in the rat testis. Specific immunostaining demonstrated that the kininogenase tissue kallikrein was present in round and elongated spermatids. Leydig cells, Sertoli cells, peritubular cells, spermatogonia and spermatocytes were not stained. Bradykinin in the supernatant of Sertoli cell cultures was effectively degraded. The resulting metabolites were analysed by high-performance liquid chromatography (HPLC). Specific protease inhibition in the degrading experiments confirmed the occurrence of several metalloproteases on Sertoli cell membranes, including neutral metalloendopeptidases (NEP 24.11 and NEP 24.15), kininase type II (angiotensin converting enzyme, ACE), and kininase type I (metallocarboxypeptidase). Northern blots hybridized with a bradykinin B2 receptor probe showed the presence of B2 receptor mRNA in testis homogenate and Sertoli cell extract. All components of the kallikrein-kinin system are present within the seminiferous epithelium of the rat. Therefore, this paracrine peptide system may play a role in the regulation of Sertoli cell function or in the Sertoli cell-germ cell crosstalk.
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PMID:Elements of the kallikrein-kinin system are present in rat seminiferous epithelium. 1061 98

The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikrein-kinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikrein-kinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.
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PMID:Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides. 1082 95

Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.
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PMID:Increased kallikrein expression protects against cardiac ischemia. 1102 68

There are few studies regarding the evaluation of the kinin system in patients with systemic lupus erythematosus (SLE). In this study, we evaluated the plasma levels of high-molecular weight kininogen (HKg), low-molecular weight kininogen (LKg) and plasma kallikrein; the plasma activity of tissue kallikrein and kininase II, and urinary kallikrein and kininase II activities in patients presenting with active lupus nephritis. A total of 30 patients (29 women) aged 21-62 years (median = 39) and 30 controls matched to the patients for sex and age were studied. Patients presenting with other underlying diseases or using drugs, which could interfere with the kinin system, were excluded. HKg and LKg levels were indirectly evaluated by ELISA. Plasma kallikrein, tissue kallikrein, and kininase II were evaluated by their enzymatic activity on selective substrates. The Mann-Whitney test was used for statistical analysis. HKg, LKg and plasma kallikrein levels were significantly increased in patients (p < 0.001, for each comparison). Similarly, tissue kallikrein and kininase II activities were significantly increased in plasma and urine of patients (p <0.001, for each comparison). In urine, the activities of tissue kallikrein and kininase II were at least seven times higher than those seen in the plasma of patients. These results indicate that the kinin system is involved in the acute manifestations of lupus nephritis. Kinins may facilitate immunecomplex deposition and may induce the release of other pro-inflammatory mediators, including cytokines actively involved in the pathogenesis of lupus nephritis.
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PMID:Kinin system in lupus nephritis. 1156 80

The role of bradykinin in the cardiovascular effects of angiotensin converting enzyme inhibitors remains difficult to establish. On their haemodynamic effects, bradykinin acts during their acute administration, participating in their vasodilatation action, while during their chronic administration they act slightly or not at all. On their trophic effects, the action of the tissue kallikrein-kinin system, suggested by the results of animal experimentation, is yet to be demonstrated in man. For their effects on cardiovascular morbidity and mortality the role of bradykinin remains under discussion. Nevertheless, besides ACE inhibitors, the other therapeutic agents which increase the levels of bradykinin, such as neutral endopeptidase inhibitors, have a significant field of development in the course of cardiovascular pathologies.
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PMID:[Effects of bradykinin in the cardiovascular effects of angiotensin-converting enzyme inhibitors]. 1193 54

The generation of kinins on the surface of vascular endothelium has been postulated in two pathways involving plasma kallikrein and tissue kallikrein; the former pathway has been well documented, but the latter is controversial. To clarify the presence of a kinin-generating system on endothelium, we examined whether human umbilical vein endothelial cells (HUVEC) synthesize and release tissue kallikrein in vitro. Kallikrein-like activity hydrolyzing a peptide Pro-Phe-Arg-4-methyl-coumaryl-7-amide was detected in the culture medium of HUVEC and was inhibited by aprotinin but not by soybean trypsin inhibitor. Western blotting of HUVEC medium using anti-human tissue kallikrein antibodies demonstrated the release of tissue kallikrein from HUVEC, and the reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blotting revealed the expression of tissue kallikrein mRNA in HUVEC. HUVEC metabolically labeled with [35S]methionine released radioactive proteins corresponding to tissue kallikrein. RT-PCR also showed the expression of low-molecular-weight kininogen (L-kininogen) mRNA in HUVEC. The cGMP levels in HUVEC were significantly elevated by the incubation with angiotensin converting enzyme inhibitor, lisinopril, and the elevation was completely inhibited by aprotinin or bradykinin B2-receptor antagonist, FR172357. These results suggest that the endothelial cells continuously release an active form of tissue kallikrein which enables generation of kinins on the vascular endothelium.
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PMID:Tissue kallikrein is synthesized and secreted by human vascular endothelial cells. 1258 67

The therapeutic use of angiotensin converting enzyme (ACE) inhibitors, at a large scale, in arterial hypertension has showed that these molecules can exert beneficial effects on insulin sensitivity and may reduce the occurrence of type 2 diabetes mellitus. One hypothesis explaining these effects of ACE inhibitors may relate to their capacity to interfere with bradykinin (BK) metabolism and action. BK may participate in the regulation of substrate utilization by several tissues by improving blood flow and substrate delivery to the tissues and also by promoting translocation of glucose transporters. Moreover, BK has been shown to increase phosphorylation of insulin receptor and its cell substrates. BK also appears to improve the release of insulin. Furthermore, insulin may activate the kallikrein-kinin system, which consequently may increase its metabolic effects. However, in experimental diabetes mellitus, BK can participate to the inflammatory reaction leading to Langerhans islets destruction. In diabetes, whereas tissue kallikrein mRNA levels were reduced in several organs, an overexpression of kinin receptors, an increase in plasma levels of kininogens and kallikrein and an activation of the kinin system have all been reported. Lastly, kinins may be involved in the development of diabetic nephropathy. Reduction of kinin metabolism by ACE inhibitors might be involved in the beneficial effects exerted by these compounds in diabetic kidney functions.
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PMID:The kallikrein-kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity. 1525 31

Bradykinin and Lys-bradykinin are potent peptide mediators implicated in several physiopathological effects in mammals. They act through activation of G-protein-coupled constitutive B(2) or inducible kinin B(1) receptors linked to signaling pathways involving increased intracellular Ca(++) concentrations and/or release of mediators including arachidonic acid metabolites, NO and EDHF. In the cardiovascular system, the kallikrein-kinin system exerts a fine control of vascular smooth muscle tone and arterial blood pressure, and plays a significant cardioprotective effect. This has been lately confirmed in experimental studies employing transgenic mice overexpressing human tissue kallikrein and animals with knockout of kinin B(1) and B(2) receptor gene. Disturbances in this system are associated with arterial hypertension, myocardial ischaemia and other clinical complications. Inhibitors of kininase II (angiotensin-converting enzyme) have been prescribed successfully to patients with cardiovascular diseases, but there is still a great interest in developing drugs or pharmacological strategies that augment the activity of kininogen-kallikrein-kinin system in pathological conditions. Delivery of adenovirus vector containing the human tissue kallikrein gene (gene kallikrein therapy) has emerged as a great potential to satisfy these conditions. This review provides a summary of plasma and tissue kallikrein-kinin system, focusing on the pharmacological properties, kinin receptors and drugs reported to interfere with their actions. The modulatory effects of the kallikrein-kinin system on cardiovascular system, particularly in regulating smooth muscle tone and arterial blood pressure and in preventing myocardium ischaemia have also been explored in the review.
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PMID:The plasma and tissue kininogen-kallikrein-kinin system: role in the cardiovascular system. 1563 42

Kallikreins cleave plasma kininogens to release the bioactive peptides bradykinin (BK) or kallidin (Lys-BK). These peptides then activate widely disseminated B2 receptors with consequences that may be either noxious or beneficial. We used cultured cells to show that kallikrein can bypass kinin release to activate BK B2 receptors directly. To exclude intermediate kinin release or kininogen uptake from the cultured medium, we cultured and maintained cells in medium entirely free of animal proteins. We compared the responses of stably transfected Chinese hamster ovary (CHO) cells that express human B2 receptors (CHO B2) and cells that coexpress angiotensin I-converting enzyme (ACE) as well (CHO AB). We found that BK (1 nM or more) and tissue kallikrein (1-10 nM) both significantly increased release of arachidonic acid beyond unstimulated baseline level. An enzyme-linked immunoassay for kinin established that kallikrein did not release a kinin from CHO cells. We confirmed the absence of kininogen mRNA with RT-PCR to rule out kininogen synthesis by CHO cells. We next tested an ACE inhibitor for enhanced BK receptor activation in the absence of kinin release and synthesized an ACE-resistant BK analog as a control for these experiments. Enalaprilat (1 microM) potentiated kallikrein (100 nM) in CHO AB cells but was ineffective in CHO B2 cells that do not bear ACE. We concluded that kallikrein activated B2 receptors without releasing a kinin. Furthermore, inhibition of ACE enhanced the receptor activation by kallikrein, an action that may contribute to the manifold therapeutic effects of ACE inhibitors.
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PMID:Kallikrein activates bradykinin B2 receptors in absence of kininogen. 1627 98

An intensification of the local cardiac kallikrein-kinin system (KKS) is thought to delay the development of cardiac failure. Since myocardial infarction is one of the leading causes of death in the developed countries, the role of the kallikrein-kinin system was studied in numerous experimental studies focusing on this disease using strategies like kallikrein gene transfer, tissue kallikrein infusion and/or by use of human kallikrein over expressing animals. These studies suggested that the kallikrein-kinin system increases coronary blood flow, decreases infarct size and left ventricular remodeling post myocardial infarction. This is of special interest since pharmacological inhibition of the angiotensin converting enzyme acts not only by reducing angiotensin II levels, but also by preventing enzymatic breakdown of kinins, suggesting that the kallikrein-kinin system is part of ACE inhibition effects. Here we review the current concept of the kallikrein-kinin system during myocardial infarction with special regard to its effects on angiogenesis and myocardial regeneration.
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PMID:New perspective on the tissue kallikrein-kinin system in myocardial infarction: role of angiogenesis and cardiac regeneration. 1818 18


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