Tissue Kallikrein Activity and Kinin Release in Human Endothelial Cells

Graf, Kristof; Gräfe, Michael; Auch-Schwelk, Wolfgang; Baumgarten, C; Scheffer, Hester J.; Hildebrandt, Alfred G.; Fleck, Eckart

doi:10.1515/cclm.1994.32.7.495

Cited by 4 publications

(4 citation statements)

References 20 publications

(13 reference statements)

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“…The presence of TK mRNA observed in TK ϩ/ϩ arteries is in agreement with previous studies performed with blood vessels and cultured vascular endothelial and smooth muscle cells. 14,20,34,35 Bradykinin B 2 receptors are functional in this blood vessel given that bradykinin is seen to cause an endothelium-dependent increase in diameter, which is blocked by the B 2 receptor Figure 5. Flow-dependent responses (m) in carotid arteries from TK ϩ/ϩ (top) and TK Ϫ/Ϫ mice (bottom).…”

Section: Discussionmentioning

confidence: 99%

Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein–Knockout Mice

Bergaya

Meneton

Bloch-Faure

et al. 2001

Circulation Research

106

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Flow-dependent dilation is a fundamental mechanism by which large arteries ensure appropriate blood supply to tissues. We investigated whether or not the vascular kallikrein-kinin system, especially tissue kallikrein (TK), contributes to flow-dependent dilation by comparing wild-type and TK-knockout mice in which the presence or absence of TK expression was verified. We examined in vitro changes in the outer diameter of perfused carotid arteries from TK / and TK / mice. In both groups, exogenous bradykinin caused a similar dilation that was abolished by the B 2 receptor antagonist HOE-140, as well as by the NO synthase inhibitor N-nitro-L-arginine methyl ester. However, purified kininogen dilated only TK / arteries, demonstrating the essential role of TK in the vascular formation of kinins. In TK / arteries, increasing intraluminal flow caused a larger endothelium-dependent dilation than that seen in TK /. In both strains the flow response was mediated by NO and by endothelium-derived hyperpolarizing factor, whereas in TK / vasoconstrictor prostanoids participated as well. HOE-140 impaired flow-dependent dilation in TK / arteries while showing no effect in TK /. This compound reduced the flow response in TK / arteries to a level similar to that in TK /. After NO synthase inhibition, HOE-140 no longer affected the response of TK /. Impaired flow-dependent dilation was also observed in arteries from knockout mice lacking bradykinin B 2 receptors as compared with wild-type animals. This study demonstrates the active contribution of the vascular kallikrein-kinin system to one-third of the flow-dependent dilation response via activation of B 2 receptors coupled to endothelial NO release. (Circ Res. 2001;88: 593-599.) Key Words: bradykinin kininogen flow-dependent vasodilation endothelium bradykinin B 2 receptor L arge arteries accommodate changes in blood flow by increasing their diameter via the release of endothelial factors such as NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). 1-4 This flow-dependent dila-tion (FDD) response represents a fundamental physiological mechanism that acts to oppose vasoconstriction, normalize shear stress, and ensure appropriate blood supply to tissues. Bradykinin modulates vascular smooth muscle tone by stimulating endothelial B 2 receptors and releasing NO and other mediators. 5-7 Bradykinin is a product of the cleavage of high and low molecular weight kininogens resulting from activation of proteases such as plasma and tissue kallikreins (TKs), cathepsins, or calpains. 8-12 The presence in the vessel wall of kininogens and kallikrein-like activities, including TK, suggests the existence of an endogenous vascular kinin-generating system, different from the circulating plasma kallikrein-kinin system. 13-16 However, the physiological role of the vascular kallikrein-kinin system itself has not been fully established because of the possible contribution of preadsorbed plasma kallikrein to vascular kinin formation and the lack of specific inhibitors of TK. 17-19 ...

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Section: Discussionmentioning

confidence: 99%

Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein–Knockout Mice

Bergaya

Meneton

Bloch-Faure

et al. 2001

Circulation Research

106

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“…TKs are secreted in a variety of glandular tissue, including salivary glands (3)(4)(5), colon (4), stomach (6), uterus (7), pituitary gland (8), and pancreas (9). It is also synthesized by neutrophils (10), kidney (11), and endothelial cells (12). TK function and regulation var-ies with tissue localization (2).…”

mentioning

confidence: 99%

Bronchial Tissue Kallikrein Activity Is Regulated by Hyaluronic Acid Binding

Forteza

Lauredo²,

Abraham³

et al. 1999

Am J Respir Cell Mol Biol

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Tissue kallikrein (TK) is secreted by serous cells of tracheobronchial submucosal glands and plays a role in allergic airway responses. To better understand the regulation of TK, we used primary cultures of submucosal gland cells that release TK upon stimulation. Media from cultures stimulated with chymase (10(-7) M) showed increased TK activity (0.50 +/- 0.22 mU/ml mean +/- standard error) in comparison with the control group (0.08 +/- 0.02 mU/ml). The increased TK activity was significantly correlated with increases in the levels of the serous cell marker, secretory leukoprotease inhibitor. Anion exchange chromatography of the conditioned culture media showed that TK activity eluted as a broad peak between 1.6 and 1.8 M NaCl, unlike the reported elution (0.3 to 0.6 M NaCl) of kallikreins from other tissues, suggesting that secreted bronchial TK was bound to a negatively charged molecule. Hyaluronidase digestion increased TK activity in both pre- and post-chymase-stimulated culture media, whereas no such change was seen after samples were digested with heparinase or chondroitinase ABC. Further, after hyaluronidase digestion of media, TK eluted from an anion exchange column between 0.3 and 0.6 M NaCl. Enzymatic detection of TK after nondenaturing gel electrophoresis showed that hyaluronidase digestion also reduced the electrophoretic heterogeneity of TK to a single band, whereas adding back hyaluronic acid (HA) to hyaluronidase-digested samples restored the original heterogeneity. Finally, TK activity bound to HA-Sepharose and could be eluted with HA. These studies show that primary cultures of ovine submucosal gland cells secrete TK in a regulated fashion, and that secreted TK binds to HA. This binding reduces TK enzymatic activity; therefore, factors that affect HA turnover could modify the TK activity in the airway lumen. These events could be important in the regulation of kinin-mediated airway inflammation.

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“…KLK1 activity was assessed by the colorimetric measurement of the release of 4-nitroaniline [15]. Briefly, 20 µL of Standard (0.1, 0.25, 0.5, 1, 2, 4, 8 mU porcine tissue kallikrein; Sigma Aldrich Corporation; St. Louis, MO, USA) or sample were diluted in a total volume of 150 µL (0.1 mol/L Tris, 0.234 mol/L NaCl, pH 7.8).…”

Section: Measurement Of Tissue Kallikrein Activity (Klk1) In Endothelmentioning

confidence: 99%

“…In particular, low doses of ROS, by reducing thiolic residues in transmembrane receptors, induce the activation of downstream protection pathways, whereas high doses of ROS, by affecting the tertiary structure of these receptors, inhibit the activation of protective mechanisms [13,14]. Furthermore, it has been reported that endothelial cells are able to synthesize and release Bk through the activity of an endothelial isoform of tissue kallikrein that cleaves endogenous kininogen [15,16]. However, it has not yet been clarified whether endothelium produces Bk during PC.…”

Section: Introductionmentioning

confidence: 99%

Autocrine Bradykinin Release Promotes Ischemic Preconditioning-Induced Cytoprotection in Bovine Aortic Endothelial Cells

Bellis

Sorriento²,

Fiordelisi³

et al. 2020

IJMS

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The aims of this study were to assess whether ischemic preconditioning (PC) induces bradykinin (Bk) synthesis in bovine aortic endothelial cells (bAECs) and, if so, to explore the molecular mechanisms by which this peptide provides cytoprotection against hypoxia. PC was induced by exposing bAECs to three cycles of 15 min of hypoxia followed by 15 min of reoxygenation. Bk synthesis peaked in correspondence to the early and late phases of PC (10−12 M and 10−11 M, respectively) and was abolished by a selective tissue kallikrein inhibitor, aprotinin. Stimulation with exogenous Bk at concentrations of 10−12 M and 10−11 M reduced the cell death induced by 12 h of hypoxia by 50%. Pretreatment with HOE−140, a Bk receptor 2 (BKR2) inhibitor, in bAECs exposed to 12 h of hypoxia, abrogated the cytoprotective effect of early and late PC, whereas des-Arg-HOE-140, a Bk receptor 1 (BKR1) inhibitor, affected only the late PC. In addition, we found that PC evoked endocytosis and the recycling of BKR2 during both the early and late phases, and that inhibition of these pathways affected PC-mediated cytoprotection. Finally, we evaluated the activation of PKA and Akt in the presence or absence of BKR2 inhibitor. HOE-140 abrogated PKA and Akt activation during both early and late PC. Consistently, BKR2 inhibition abolished cross-talk between PKA and Akt in PC. In bAECs, Bk-synthesis evoked by PC mediates the protection against both apoptotic and necrotic hypoxia-induced cell death in an autocrine manner, by both BKR2- and BKR1-dependent mechanisms.

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Tissue Kallikrein Activity and Kinin Release in Human Endothelial Cells

Cited by 4 publications

References 20 publications

Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein–Knockout Mice

Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein–Knockout Mice

Bronchial Tissue Kallikrein Activity Is Regulated by Hyaluronic Acid Binding

Autocrine Bradykinin Release Promotes Ischemic Preconditioning-Induced Cytoprotection in Bovine Aortic Endothelial Cells

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