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Tissue Kallikrein Is Synthesized and Secreted by Human Vascular Endothelial Cells

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Tissue Kallikrein Is Synthesized and Secreted by Human Vascular Endothelial Cells Biochimica et Biophysica Acta 1593 (2003) 231–238 www.bba-direct.com Tissue kallikrein is synthesized and secreted by human vascular endothelial cells Katsutoshi Yayama, Naomi Kunimatsu, Yumiko Teranishi, Masaoki Takano, Hiroshi Okamoto* Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Ikawadani-cho, Nishi-ku, Kobe 651-2180, Japan Received 12 August 2002; received in revised form 19 November 2002; accepted 26 November 2002 Abstract 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. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Kallikrein; Endothelial cell; Bradykinin; HUVEC 1. Introduction Kinins are generated in the circulation by at least two different routes involving plasma kallikrein and tissue kal- The vascular tissue has been identified to be a paracrine likrein, respectively. Plasma kallikrein (EC 3.4.21.34), and autocrine organ regulating blood flow by various vaso- which is activated from the circulating zymogen, prekallik- active factors. Kinins, such as bradykinin and kallidin, rein, on the surface of endothelial cells during the initiation generated in plasma mainly act on endothelial cells via B2- of intrinsic coagulation then cleaves high-molecular-weight receptor to release various agents associated with vascular kininogen (H-kininogen) to liberate bradykinin [2,3]. On the tonus and blood coagulation, such as prostaglandins, nitric other hand, tissue kallikrein (EC 3.4.21.35) is a serine oxide (NO), cytokines, and tissue plasminogen activator, protease (hK1) encoded by one of the kallikrein gene family resulting in the maintenance of circulation homeostasis [1]. consisting of at least 15 genes (KLK1–KLK15) in humans [4]. Tissue kallikrein is distinct from plasma kallikrein in the origins of synthesis and the physicochemical properties, such Abbreviations: HUVEC, human umbilical vein endothelial cells; HAEC, human coronary artery endothelial cells; L-kininogen, low-molecular- as molecular size, substrate specificity, and the susceptibility weight kininogen; H-kininogen, high-molecular-weight kininogen; SDS- to various inhibitors [1]. Tisssue kallikrein cleaves L- and H- PAGE, sodium dodecylsulfate polyacrylamide gel electrophoresis; RT-PCR, kininogens to liberate Lys-bradykinin which is rapidly con- reverse transcription-polymerase chain reaction; FCS, fetal calf serum; verted to bradykinin by aminopeptidases in plasma [1]. IBMX, 3-isobutyl-1-methyl-xanthine; EBM, endothelial basal medium; Low levels of tissue kallikrein have been detected in MCA, 4-methyl-coumaryl-7-amide; HBSS, Hank’s balanced salt solution * Corresponding author. Tel.: +81-78-974-4403; plasma [5]. Since the major sources of tissue kallikrein are fax: +81-78-974-5689. exocrine glands such as the kidney, pancreas, and salivary E-mail address: [email protected] (H. Okamoto). gland, the origin of tissue kallikrein detected in plasma was 0167-4889/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0167-4889(02)00393-2 232 K. Yayama et al. / Biochimica et Biophysica Acta 1593 (2003) 231–238 suggested to be these organs and tissues [6]. However, 2.3. Assay of tissue kallikrein-like enzyme activity in the several findings have suggested that the tissue kallikrein– HUVEC-conditioned medium kinin system is present within the vascular wall; a kallikrein- like kininogenase activity is present in and released from The tissue kallikrein-like enzyme activity was assayed vascular tissue [7,8], and the expressions of mRNAs for using the synthetic peptide Pro-Phe-Arg-MCA as the sub- tissue kallikrein and kininogens were also demonstrated in strate [13]. HUVEC in 75-cm2 dishes were washed twice vascular tissues [9]. Furthermore, the immunoreactivity of with Ca2+,Mg2+-free Hank’s balanced salt solution (HBSS), tissue kallikrein was detected in human endothelial cells then cultured in EBM. The conditioned medium (about 7 [10,11], and the endothelial and smooth muscle cells in ml) was dialyzed overnight against distilled water at 4 jC, human blood vessels were demonstrated to be the sites of then the dialyzate was lyophilized. The lyophilizate was synthesis of tissue kallikrein by means of in situ hybrid- dissolved in 0.5 ml of 0.1 M Tris–HCl, pH 7.8, containing ization [11]. Recently, Dedio et al. [12] reported that human 10 Ag/ml of bovine serum albumin and 0.1 M NaCl (Buffer umbilical vein endothelial cells (HUVEC) synthesized and 1). The sample (50–100 Al) was mixed with Buffer 1 in a stored tissue kallikrein with molecular sizes of about 50 kDa total volume of 0.5 ml and incubated for 5 min at 37 jC recognized by anti-tissue kallikrein antibodies, suggesting with or without 20 Ag of aprotinin. Ten microliters of 5 mM that the endothelial cells are a source of tissue kallikrein in Pro-Phe-Arg-MCA dissolved in dimethylsulfoxide was the vascular wall. However, evidence that tissue kallikrein added, then the mixture was further incubated for 1 h. synthesized by HUVEC is released from the endothelial Reaction was terminated by adding 2 ml of 12% acetic cells as an active form of the enzyme has not been provided. acid, and the liberated AMC was determined using a In the present study, we demonstrated that HUVEC synthe- spectrofluorometer (Hitachi F3000) at 380 nm (exitation) size and release an active form of tissue kallikrein with a and 460 nm (emission) using AMC as a standard. The molecular size of about 30 kDa, and therefore suggest that sample incubated in the presence of aprotinin was used as a there is a tissue kallikrein-dependent kinin generation on the blank. Enzyme activity was expressed as nmol AMC/mg surface of endothelial cells, which probably plays important protein of HUVEC/h. Cell protein levels were measured roles in the maintenance of circulation homeostasis. using the BCA Protein Assay Reagent (Pierce). 2.4. Western blots of human tissue kallikrein 2. Materials and methods Conditioned medium (500 ml) of HUVEC was harvested, 2.1. Materials then applied to a column of aprotinin–agarose (1.5Â2.0 cm) equilibrated with 50 mM Tris–HCl, pH 8.0, containing 0.5 HUVEC, human coronary artery endothelial cells M NaCl. The column was washed with 20 ml of the (HAEC), human coronary artery smooth muscle cells equilibrium buffer, and the adsorbed proteins were eluted (HSMC), endothelial basal medium (EBM), and endothelial with 0.1 M glycine–HCl, pH 2.5. The eluate was neutralized cell growth supplement were purchased from Clonetics; immediately with 1 M Tris–HCl, pH 8.5. Fractions contain- HeLa cells from Human Science Research Resources Bank ing kallikrein-like activity on the synthetic peptide Pro-Phe- (Osaka, Japan); fetal calf serum (FCS) from Invitrogen; Arg-MCA were pooled, dialyzed against distilled water at 4 rabbit anti-human tissue kallikrein from Calbiochem; His- jC, then lyophilized. The lyophilizate was resolved by tofine SAB-PO Kit from Nichirei Co. (Tokyo, Japan); sodium dodecylsulfate polyacrylamide gel electrophoresis aprotinin, aprotinin-agarose, soybean trypsin inhibitor, and (SDS-PAGE) in a 10% gel, then electrophoretically trans- 3-isobutyl-1-methyl-xanthine (IBMX) from Sigma; Pro- ferred to Immobilon-PSQ membrane (Millipore). The mem- Phe-Arg-4-methyl-coumaryl-7-amide (Pro-Phe-Arg-MCA) brane was then blocked with 10% skimmed milk followed by and 7-amino-4-methylcoumarin (AMC) from Peptide Insti- incubation with rabbit anti-human kallikrein antibody. Rab- tute, Inc. (Osaka, Japan). Tissue kallikrein purified from bit IgG on the membrane was detected by the avidin– human urine was supplied by Japan Chemical Research Co. biotin–peroxidase complex method according to the instruc- (Kobe, Japan). FR172357, a specific B2-receptor antago- tion manual issued by Bio-Rad Laboratories. nist, and lisinopril were supplied by Fujisawa Pharmaceut- ical Co. (Osaka, Japan) and Shionogi & Co. (Osaka, Japan), 2.5. Reverse transcription-polymerase chain reaction (RT- respectively. PCR) Southern blot analysis of tissue kallikrein and low- molecular-weight kininogen (L-kininogen)
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