Kininogens revisited

Müller‐Esterl, Werner; Iwanaga, Shunsuke; Nakanishi, Shigetada

doi:10.1016/0968-0004(86)90293-8

Cited by 160 publications

(70 citation statements)

References 26 publications

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“…7 Binding of kinins to the bradykinin (BK) B2 receptor activates second messengers in target tissues and triggers a wide spectrum of biological effects such as vasodilation, vasoconstriction, increase in vascular permeability and inhibition or stimulation of cell growth. [8][9][10][11] The vasodilatory action of the kallikrein-kinin system counterbalances the vasoconstrictive action of the reninangiotensin system (RAS). The observation that urinary excretion of tissue kallikrein is significantly reduced in hypertensive patients was reported in 1934.…”

Section: Introductionmentioning

confidence: 99%

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Wang

Zhao

et al. 2004

Gene Ther

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Gene therapy of hypertension requires long-term expression of a therapeutic gene to achieve stable reduction of blood pressure. Human tissue kallikrein (HK) cleaves kininogen to produce a potent vasoactive peptide kinin, which plays an important role in the regulation of the cardiovascular and renal functions. In the present study, we have delivered human kallikrein cDNA with an rAAV vector to explore the potential therapeutic effects of kallikrein on hypertension and related secondary complications. A single tail vein injection of the rAAV-HK vector into the adult spontaneously hypertensive rats resulted in a significant reduction (12.072.55 mmHg, Po0.05, n ¼ 6, ANOVA) of the systolic blood pressure from 2 weeks after vector injection, when compared with the control rAAV-lacZ vector-injected rats. Weekly blood pressure monitoring showed stable hypertension-reduction effect throughout the course of the 20-week experiments. In addition, total urine microalbumin contents decreased as a result of rAAV-HK treatment. Histological analysis of various tissues showed remarkable amelioration of cardiovascular hypertrophy, renal injury and collagen depositions in the rAAV-treated group. Finally, persistent expression of the transgene product HK was confirmed by the enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. We conclude that rAAV-mediated HK delivery rendered a long-term and stable reduction of hypertension and protected against renal injury, cardiac remodeling in the spontaneously hypertensive rat model. Further studies are warranted for the development of a gene therapy strategy for human hypertension.

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Section: Introductionmentioning

confidence: 99%

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Wang

Zhao

et al. 2004

Gene Ther

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“…Structural analyses demonstrated that the kininogen heavy chain consists of three domains, designated D1-D3, which share a high internal homology with low-molecular weight cystatins [2,11]. The kininogens therefore were classified as family 3 of the cystatin superfamily [12].…”

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confidence: 99%

“…Similarly, the binding of kininogen via its light chain to a surface, as indicated by the binding to the model surface, heparin, did not affect the inhibitory properties of kininogen. The M~ of high-molecular-weight kininogen was determined to be 83 500 by sedimentation equilibrium measurements, in agreement with the value calculated from amino acid sequence and carbohydrate analysis.Key words: Kininogen; Cathepsin; Cystatin; Cysteine proteinase; Kinetics disulfide bond, by limited proteolysis by kallikreins, thereby releasing the kinin segment [2]. The heavy chains of HK and LK are identical, whereas the light chain of HK is substantially larger than that of LK [8].…”

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confidence: 99%

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High‐molecular‐weight kininogen binds two molecules of cysteine proteinases with different rate constants

et al. 1996

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Fluorescence titrations showed that high-molecularweight kininogen binds two molecules of papain, cruzipain and cathepsin S with high affinity. The 2:1 binding stoichiometry was confirmed by stopped-flow kinetic measurements of papain binding, which also revealed that the two sites bind the enzyme with different association rate constants (kas~,l = 23.0 X 106 M -1 s -1 and k~,2 = 3.4 X 106 M -1 s -1 ). As for low-molecular-weight kininogen, comparison of these kinetic constants with previous data for intact low-and high-molecular-weight kininogen and the separated domains indicated that the faster-binding site is also the tighter-binding site and is that of domain 3, whereas the slower-binding, lower-affinity site is on domain 2. The results further demonstrate that there is no appreciable steric interference between the two domains or by the kininogen light chain in the binding of proteinases. Similarly, the binding of kininogen via its light chain to a surface, as indicated by the binding to the model surface, heparin, did not affect the inhibitory properties of kininogen. The M~ of high-molecular-weight kininogen was determined to be 83 500 by sedimentation equilibrium measurements, in agreement with the value calculated from amino acid sequence and carbohydrate analysis.Key words: Kininogen; Cathepsin; Cystatin; Cysteine proteinase; Kinetics disulfide bond, by limited proteolysis by kallikreins, thereby releasing the kinin segment [2]. The heavy chains of HK and LK are identical, whereas the light chain of HK is substantially larger than that of LK [8].About a decade ago, kininogens were shown to be potent inhibitors of papain-like cysteine proteinases [9,10]. Structural analyses demonstrated that the kininogen heavy chain consists of three domains, designated D1-D3, which share a high internal homology with low-molecular weight cystatins [2,11]. The kininogens therefore were classified as family 3 of the cystatin superfamily [12]. Isolated domains D2 and D3 were shown to inhibit papain-like cysteine proteinases (D2 and D3) and calpain (D2), whereas domain D1 was found to lack inhibitory activity [11,13].We have recently shown that intact human LK simultaneously can bind two molecules of cysteine proteinases with high affinity [14]. In this work we demonstrate that human HK can also bind two molecules of cathepsin S, cruzipain and papain independently. Moreover, kinetic studies of papain binding showed that the two sites bound the proteinase with different rate constants. Materials and methods

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“…Sequence data have shown that the heavy chains are composed of three tandemly repeated cystatin-like domains, designated DI-D3 Muller-Ester1 et al, 1986). Domain D l contains a Ca2+-binding site but does not inhibit cysteine proteinases (Higashiyama et al, 1987).…”

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confidence: 99%

High-affinity binding of two molecules of cysteine proteinases to low-molecular-weight kininogen

et al. 1995

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Human low-molecular-weight kininogen (LK) was shown by fluorescence titration to bind two molecules of cathepsins L and S and papain with high affinity. By contrast, binding of a second molecule of cathepsin H was much weaker. The 2: 1 binding stoichiometry was confirmed by titration monitored by loss of enzyme activity and by sedimentation velocity experiments. The kinetics of binding of cathepsins L and S and papain showed the two proteinase binding sites to have association rate constants k,,,,, = 10.7-24.5 x IO6 M" s-I a nd k,,,,, = 0.83-1.4 x lo6 M" s-' . Comparison of these kinetic constants with previous data for intact LK and its separated domains indicate that the faster-binding site is also the tighter-binding site and is present on domain 3, whereas the slowerbinding, lower-affinity site is on domain 2. These results also indicate that there is no appreciable steric hindrance for the binding of proteinases between the two binding sites or from the kininogen light chain.

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Kininogens revisited

Cited by 160 publications

References 26 publications

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

High‐molecular‐weight kininogen binds two molecules of cysteine proteinases with different rate constants

High-affinity binding of two molecules of cysteine proteinases to low-molecular-weight kininogen

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