Endothelial cells contain leukotriene (LT) A4 hydrolase (LTA-H) as detected by Northern and Western blotting, but several studies have been unable to detect the activity of this enzyme. Since LTA-H could play a key role in determining what biologically active lipids are generated by activated endothelium during the inflammatory process, we studied possible mechanisms by which this enzyme may be regulated. We find that LTA-H is phosphorylated under basal conditions in human endothelial cells and in this state does not exhibit epoxide hydrolase activity (i.e. conversion of LTA4 to LTB4). LTA-H purified from endothelial cells is efficiently dephosphorylated by incubation with protein phosphatase-1 in the presence of an LTA-H peptide substrate and not at all in the absence of substrate. Under conditions that lead to dephosphorylation, protein phosphatase-1 activates the epoxide hydrolase activity of LTA-H. Using peptide mapping and site-directed mutagenesis, we have identified serine 415 as the site of phosphorylation of LTA-H by a kinase found in endothelial cell cytosol. In parallel, we have studied a human lung carcinoma cell line that expresses active LTA-H. Although these cells have cytosolic kinases that phosphorylate recombinant LTA-H, they do not target serine 415 and thus do not inhibit LTA-H activity. We believe that LTA-H is regulated in intact cells by a kinase/phosphatase cycle and further that the kinase in endothelial cells specifically recognizes and phosphorylates a regulatory site in the LTA-H. Endothelial cells contain leukotriene (LT) A4 hydrolase (LTA-H) as detected by Northern and Western blotting, but several studies have been unable to detect the activity of this enzyme. Since LTA-H could play a key role in determining what biologically active lipids are generated by activated endothelium during the inflammatory process, we studied possible mechanisms by which this enzyme may be regulated. We find that LTA-H is phosphorylated under basal conditions in human endothelial cells and in this state does not exhibit epoxide hydrolase activity (i.e. conversion of LTA4 to LTB4). LTA-H purified from endothelial cells is efficiently dephosphorylated by incubation with protein phosphatase-1 in the presence of an LTA-H peptide substrate and not at all in the absence of substrate. Under conditions that lead to dephosphorylation, protein phosphatase-1 activates the epoxide hydrolase activity of LTA-H. Using peptide mapping and site-directed mutagenesis, we have identified serine 415 as the site of phosphorylation of LTA-H by a kinase found in endothelial cell cytosol. In parallel, we have studied a human lung carcinoma cell line that expresses active LTA-H. Although these cells have cytosolic kinases that phosphorylate recombinant LTA-H, they do not target serine 415 and thus do not inhibit LTA-H activity. We believe that LTA-H is regulated in intact cells by a kinase/phosphatase cycle and further that the kinase in endothelial cells specifically recognizes and phosphorylates a regulatory site in the LTA-H. Leukotriene (LT) 1The abbreviations used are: LT, leukotriene; LTA4 and LTB4, leukotriene A4 and B4, respectively; LTA-H, leukotriene A4hydrolase; PMNL, polymorphonuclear leukocytes; EC, endothelial cell(s); HUVEC, human umbilical vein endothelial cell(s); DMEM, Dulbecco's modified Eagle's medium; PAGE, polyacrylamide gel electrophoresis; HPLC, high performance liquid chromatography; RP-HPLC, reverse phase HPLC; PCR, polymerase chain reaction; Bis-Tris, bis[2-hydroxyethyl]imino-tris[hydroxymethyl]methane; PGB2, prostaglandin B2.A4 hydrolase (LTA-H; EC 3.3.2.6) is a zinc metalloenzyme that catalyzes the hydrolysis of LTA4 to yield the dihydroxyarachidonic acid metabolite, LTB4 (1Shimizu T. Int. J. Biochem. 1988; 20: 661-666Crossref PubMed Scopus (31) Google Scholar, 2Haeggström J.Z. Wetterholm A. Shapiro R. Vallee B.L. Samuelsson B. Biochem. Biophys. Res. Commun. 1990; 172: 965-970Crossref PubMed Scopus (103) Google Scholar, 3Haeggström J.Z. Wetterholm A. Vallee B.L. Samuelsson B. Biochem. Biophys. Res. Commun. 1990; 173: 431-437Crossref PubMed Scopus (112) Google Scholar). The major source and site of action of this potent inflammatory lipid is the polymorphonuclear leukocyte (PMNL), where LTB4 plays a key role in regulating PMNL function including chemotaxis (4Ford-Hutchinson A.W. Bray M.A. Doig M.V. Shipley M.E. Smith M.J.H. Nature. 1980; 286: 264-265Crossref PubMed Scopus (1585) Google Scholar), adhesion to endothelium (5Gimbrone Jr., M.A. Brock A.F. Schafer A.I. J. Clin. Invest. 1984; 74: 1552-1555Crossref PubMed Scopus (153) Google Scholar, 6Tonnesen M.G. Anderson D.C. Springer T.A. Knedler A. Avdi N. Henson P.M. J. Clin. Invest. 1989; 83: 637-646Crossref PubMed Scopus (186) Google Scholar), superoxide anion generation (7Cunningham F.M. Shipley M.E. Smith M.J.H. J. Pharm. Pharmacol. 1980; 32: 377-380Crossref PubMed Scopus (46) Google Scholar, 8Claesson H.-E. Feinmark S.J. Biochim. Biophys. Acta. 1984; 804: 52-57Crossref PubMed Scopus (30) Google Scholar), and degranulation (8Claesson H.-E. Feinmark S.J. Biochim. Biophys. Acta. 1984; 804: 52-57Crossref PubMed Scopus (30) Google Scholar, 9O'Flaherty J.T. Wykle R.L. McCall C.E. Shewmake T.B. Lees C.J. Thomas M. Biochem. Biophys. Res. Commun. 1981; 101: 1290-1296Crossref PubMed Scopus (23) Google Scholar, 10Feinmark S.J. Lindgren J.Å. Claesson H.-E. Malmsten C. Samuelsson B. FEBS Lett. 1981; 136: 141-144Crossref PubMed Scopus (110) Google Scholar). LTA-H has been purified and cloned from a number of different tissues in several species. Immunohistochemical studies have suggested that the enzyme is widely spread, if not ubiquitous (11Izumi T. Shimizu T. Seyama Y. Ohishi N. Takaku F. Biochem. Biophys. Res. Commun. 1986; 135: 139-145Crossref PubMed Scopus (55) Google Scholar,12Ohishi N. Minami M. Kobayashi J. Seyama Y. Hata J. Yotsumoto H. Takaku F. Shimizu T. J. Biol. Chem. 1990; 265: 7520-7525Abstract Full Text PDF PubMed Google Scholar). It is interesting to note, however, that 5-lipoxygenase, the enzyme that generates LTA4, has a much more restricted distribution than LTA-H, and thus, many more cell types appear to have the ability to metabolize LTA4 than have the capacity to synthesize it. This has led several groups to study the transfer of LTA4 from PMNL to cells that lack the 5-lipoxygenase including erythrocytes (13Fitzpatrick F. Liggett W. McGee J. Bunting S. Morton D. Samuelsson B. J. Biol. Chem. 1984; 259: 11403-11407Abstract Full Text PDF PubMed Google Scholar, 14McGee J.E. Fitzpatrick F.A. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 1349-1353Crossref PubMed Scopus (134) Google Scholar), platelets (15Maclouf J.A. Murphy R.C. J. Biol. Chem. 1988; 263: 174-181Abstract Full Text PDF PubMed Google Scholar, 16Maclouf J. Murphy R.C. Henson P.M. Blood. 1989; 74: 703-707Crossref PubMed Google Scholar), endothelial cells (16Maclouf J. Murphy R.C. Henson P.M. Blood. 1989; 74: 703-707Crossref PubMed Google Scholar, 17Feinmark S.J. Cannon P.J. J. Biol. Chem. 1986; 261: 16466-16472Abstract Full Text PDF PubMed Google Scholar, 18Ibe B.O. Campbell W.B. Biochim. Biophys. Acta. 1988; 960: 309-321Crossref PubMed Scopus (32) Google Scholar, 19Feinmark S.J. Am. Rev. Respir. Dis. 1992; 146: S51-S55Crossref PubMed Google Scholar), and vascular smooth muscle (20Feinmark S.J. Cannon P.J. Biochim. Biophys. Acta. 1987; 922: 125-135Crossref PubMed Scopus (51) Google Scholar). Similar transcellular metabolism has been demonstrated in perfused organ studies, suggesting a role in cardiac and pulmonary function (21Sala A. Rossoni G. Buccellati C. Berti F. Folco G. Maclouf J. Br. J. Pharmacol. 1993; 110: 1206-1212Crossref PubMed Scopus (55) Google Scholar, 22Sala A. Aliev G.M. Rossoni G. Berti F. Buccellati C. Burnstock G. Folco G. Maclouf J. Blood. 1996; 87: 1824-1832Crossref PubMed Google Scholar, 23Grimminger F. Thomas M. Obernitz R. Walmrath D. Bhakdi S. Seeger W. J. Exp. Med. 1990; 172: 1115-1125Crossref PubMed Scopus (18) Google Scholar, 24Grimminger F. Kreusler B. Schneider U. Becker G. Seeger W. J. Immunol. 1990; 144: 1866-1872PubMed Google Scholar). We have focused on endothelial cells (EC), because the interaction of PMNL with the endothelium is the critical initiating step of the inflammatory process and because LTB4 induces PMNL accumulation in the extravascular space and initiates the PMNL-dependent component of edema formation. Our earliest studies demonstrated that porcine aortic endothelial cells could metabolize LTA4 to LTC4 but not to LTB4 (17Feinmark S.J. Cannon P.J. J. Biol. Chem. 1986; 261: 16466-16472Abstract Full Text PDF PubMed Google Scholar), and later work extended these observations to other endothelial cell types including human umbilical vein endothelial cells (HUVEC) (25Feinmark S.J. Methods Enzymol. 1990; 187: 559-567Crossref PubMed Scopus (10) Google Scholar). If EC contain active LTA-H, the presentation of LTA4 by activated, marginal PMNL could provide an important source of substrate for EC LTB4 synthesis. Unregulated, this pathway could lead to uncontrolled synthesis of this bioactive lipid and result in inappropriate accumulation of PMNL and other manifestations of inflammation. Therefore, it has been proposed that EC may have a mechanism for regulating the activity of LTA-H (19Feinmark S.J. Am. Rev. Respir. Dis. 1992; 146: S51-S55Crossref PubMed Google Scholar). It is this question that we address in the present report. Human umbilical vein endothelial cells were cultured as previously reported (25Feinmark S.J. Methods Enzymol. 1990; 187: 559-567Crossref PubMed Scopus (10) Google Scholar). Cells were maintained in M-199 supplemented with 20% fetal bovine serum, endothelial cell growth supplement (3 μg/ml), and heparin (2 units/ml) in Petri dishes coated with 0.2% gelatin. Cells were grown at 37 °C in a humidified atmosphere of 95% air and 5% CO2. HUVEC were used in first to third passages. EA.hy 926 and A549 cells were kindly provided by Dr. Cora-Jean Edgell (University of North Carolina, Chapel Hill, NC). EA.hy 926 is a hybridoma line formed by the fusion of HUVEC with the human lung carcinoma cell line, A549. These cells have proven to be a good model for HUVEC in many studies (26Brown K.A. Vora A. Biggerstaff J. Edgell C.-J.S. Oikle S. Mazure G. Taub N. Meager A. Hill T. Watson C. Dumonde D.C. J. Immunol. Methods. 1993; PubMed Scopus (55) Google Scholar, C.-J.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). EA.hy 926 cells were maintained in Dulbecco's modified Eagle's supplemented with fetal C.-J.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). A549 cells were cultured in the presence of in supplemented with 5% fetal bovine as M. Smith B. A. W. G. Int. J. PubMed Scopus Google Scholar). on by were to to the of H. T. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of the with The were LTA-H recombinant the from cultured HUVEC, EA.hy 926 and A549 cells to the acid N. Biochem. 1987; PubMed Scopus Google on a to by and with The were with an from the LTA-H M. Minami Y. Y. H. S. Ohishi N. Shimizu T. Seyama Y. FEBS Lett. 1988; PubMed Scopus (30) Google Scholar). The were by to the to the to a of and with the at The with with for at and for at °C in with the to EC A549 were with and in the human (2 LTA4 as the by of LTA4 N. T. Seyama Y. Shimizu T. Methods Enzymol. 1990; 187: PubMed Scopus Google and for at 37 °C in a 5% The with as and the were at °C for at by and the under The in phase and by reverse phase a (3 at with acid of LTA4 were detected by at EC were from dishes with a and in at The cells were by with a model cycle The cell by the at for at The enzyme purified by The in and several of the at The and to an anion with on a were with a of from to at a of LTA-H were identified by the activity of the enzyme as LTA-H found in were and the to by LTA-H further purified from the by on a were in Bis-Tris, and with a of at a of were for and active were by and in LTA-H in as M. Minami Y. Y. H. S. Ohishi N. Shimizu T. Seyama Y. FEBS Lett. 1988; PubMed Scopus (30) Google Scholar). The enzyme purified from as LTA-H in with human (2 and LTA4 at 37 °C for The by as The at °C for at and protein by LTB4 by on a with acid at a of The at and LTB4 by with a generated from of The of by of The activity by recombinant LTA-H with in with bovine in at 37 °C for at and a on a hydrolysis of the substrate for by the of enzyme. were with and in the were more and with this and at 37 the and the cells were with The cells were of bovine and with and The cells were further by and the by of the at for The by incubation with by protein of the with recombinant LTA-H were with LTA-H on a for at to and the incubation at The were by and with bovine and with The were in and the were by were to and the LTA-H identified and from the The of the LTA-H with and the protein with at °C for The to a and to in a The in of acid acid and the were by to the of T. Methods Enzymol. PubMed Scopus Google Scholar). The first for at in and the a in for at The with in and at °C for The of the and the to at °C EC were from EA.hy 926 cell The cells were with and the with a EC were in a at °C and were in kinase of The cells were for cycle and a cytosolic by at at °C for to the cell of and the by the of recombinant LTA-H. LTA-H by to and used for peptide mapping J. M. D. Biochem. 1992; PubMed Scopus Google Scholar). The to LTA-H from the and The were with in acid for at 37 °C to The acid and the were with The were with for at in the the were with the were with in and the protein with at 37 °C The were from the by to a and The in and the by on a were with a from acid in to acid in at a of The at and were in by the that the for human LTA-H, used as a to the by polymerase chain The a fusion protein with at the were to this with the and were in the The a by the for the and a of LTA-H The The phosphorylated at by and and polymerase in of The step at °C by °C for °C for °C for The at The to the at °C and a of the (2 used to were on were and and the purified with The of the by of the and were to that the a for in and for site-directed The of serine 415 to with the to the and the and were in were grown in to a of at and were by the of and were purified from the of by and anion as by an The with of by with of purified enzyme to the which with The were by the of peptide at were for activity as The active were and the to by The of the protein by with In the of the protein as LTA-H by with with EC A549 cell as the at 37 °C for and by of kinase purified from the by an and by were and to to the on a are as the the were by a where by a of of were the that LTA-H activity not detected in endothelial we for the presence of and enzyme protein in these Northern and Western demonstrated the presence of LTA-H in HUVEC and in the endothelial cell line, EA.hy the human lung carcinoma line, that as the fusion for the EA.hy 926 for LTA-H and protein We these cells for the presence of LTA-H activity in an that the of LTB4 from HUVEC not S.J. Methods Enzymol. 1990; 187: 559-567Crossref PubMed Scopus (10) Google EA.hy 926 on the other LTA4 to LTB4 be that the absence of LTA-H activity not to of the cells to LTA4 the cell we these in cell and on purified enzyme from these The in the intact LTA-H purified from HUVEC and EA.hy 926 the enzyme from A549 cells LTA4 to LTB4 not of the acid of LTA-H that the enzyme phosphorylation if the of the purified EC enzyme be to a by a we HUVEC with the and the LTA-H by The by to and to LTA-H under these that the enzyme is phosphorylated in intact HUVEC not purified from HUVEC in for acid The acid in this were with EA.hy 926 not the of LTA-H we the peptide of recombinant LTA-H phosphorylated in by the in cell from EA.hy 926 cell LTA-H with as under and the were by with major and These were by the of LTA-H phosphorylated by A549 different Although phosphorylation on a serine not these that the kinases of the cell types different in the LTA-H. We focused on the that in the and peptide and contain a serine The peptide from of LTA-H phosphorylated by EC identified by to be the and thus the phosphorylated serine The recombinant LTA-H used in earliest studies in as a fusion protein that on the M. Minami Y. Y. H. S. Ohishi N. Shimizu T. Seyama Y. FEBS Lett. 1988; PubMed Scopus (30) Google Scholar). to initiating site-directed studies, the for this recombinant LTA-H, to this with the recombinant LTA4 hydrolase and purified an Using a mutagenesis, the serine to 415 of the enzyme to and the of the by LTA-H in and purified an The of the and the the activity of the recombinant LTA-H in the LTB4 synthesis and in the of this enzyme but these were not activity of recombinant human LTA4 and in a the and were with cell from EA.hy 926 A549 in an in in the presence of were from an and by LTA-H phosphorylated by EA.hy 926 the not a substrate for the kinase in this A549 phosphorylated LTA-H at a different site as the of and LTA-H the that the kinase source for these is a cell we of the of this enzyme phosphorylation at and the that the a activity the presence of protein phosphatase-1 in these not The to have activity with and not the of Under these LTA-H kinase in EA.hy 926 the of of of LTA-H. phosphorylation of the metabolism of LTA4 to LTB4, we LTA-H with cell from EA.hy the by The protein by were with the under In these phosphorylation a 5% in LTA4 hydrolase activity and and the activity of the enzyme not and In in the activity incubation with the of phosphorylation on the activity of and LTA4 is human is and phosphorylated is human is and phosphorylated in a We purified LTA-H from HUVEC and this enzyme with protein phosphatase-1 to could the of the enzyme. under conditions that were to recombinant LTA-H that been phosphorylated in not The ability of the EC enzyme to LTA4 to LTB4 We found that EC LTA-H activity incubation with studies of metabolism in EC have to the conversion of LTA4 to LTB4 (16Maclouf J. Murphy R.C. Henson P.M. Blood. 1989; 74: 703-707Crossref PubMed Google Scholar, 17Feinmark S.J. Cannon P.J. J. Biol. Chem. 1986; 261: 16466-16472Abstract Full Text PDF PubMed Google Scholar, 18Ibe B.O. Campbell W.B. Biochim. Biophys. Acta. 1988; 960: 309-321Crossref PubMed Scopus (32) Google Scholar, 19Feinmark S.J. Am. Rev. Respir. Dis. 1992; 146: S51-S55Crossref PubMed Google Scholar). In by Claesson and H.-E. J. J. Biochem. 1988; 173: PubMed Scopus Google found of active LTA-H in HUVEC Our that EC contain LTA-H as by Northern and Western however, LTA-H purified from EC unable to the metabolism of N. Minami M. Kobayashi J. Seyama Y. Hata J. Yotsumoto H. Takaku F. Shimizu T. J. Biol. Chem. 1990; 265: 7520-7525Abstract Full Text PDF PubMed Google Scholar, J. J. Biochim. Biophys. Acta. 1989; PubMed Scopus Google and (11Izumi T. Shimizu T. Seyama Y. Ohishi N. Takaku F. Biochem. Biophys. Res. Commun. 1986; 135: 139-145Crossref PubMed Scopus (55) Google Scholar, J. M. Biochim. Biophys. Acta. 1988; PubMed Scopus Google have that LTA-H is a widely but enzyme activity detected a in activity (11Izumi T. Shimizu T. Seyama Y. Ohishi N. Takaku F. Biochem. Biophys. Res. Commun. 1986; 135: 139-145Crossref PubMed Scopus (55) Google Scholar). These lead to that a for the of LTA-H activity may (19Feinmark S.J. Am. Rev. Respir. Dis. 1992; 146: S51-S55Crossref PubMed Google Scholar). has been generated to address this is the of of LTA-H, in EC that do not synthesize It is that EC LTA4 generated by PMNL in a process as transcellular metabolism (17Feinmark S.J. Cannon P.J. J. Biol. Chem. 1986; 261: 16466-16472Abstract Full Text PDF PubMed Google Scholar). In PMNL, which synthesize LTA4 and LTB4, have been to as much as of the LTA4 generated by the A. M. S. R. Folco G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. Folco G. FEBS Lett. 1996; PubMed Scopus Google Scholar). the capacity of EC to and metabolize LTA4 generated by PMNL, the cell types are in lead to in by the for EC of LTC4 transcellular metabolism has been and (16Maclouf J. Murphy R.C. Henson P.M. Blood. 1989; 74: 703-707Crossref PubMed Google Scholar, 17Feinmark S.J. Cannon P.J. J. Biol. Chem. 1986; 261: 16466-16472Abstract Full Text PDF PubMed Google Scholar, 18Ibe B.O. Campbell W.B. Biochim. Biophys. Acta. 1988; 960: 309-321Crossref PubMed Scopus (32) Google Scholar, 19Feinmark S.J. Am. Rev. Respir. Dis. 1992; 146: S51-S55Crossref PubMed Google Scholar). if EC could LTB4 in with activated LTB4 is a potent for PMNL adhesion to EC (5Gimbrone Jr., M.A. Brock A.F. Schafer A.I. J. Clin. Invest. 1984; 74: 1552-1555Crossref PubMed Scopus (153) Google Scholar, R.L. Proc. Natl. Acad. Sci. U. S. A. 1984; PubMed Scopus Google Scholar). this lipid induces PMNL to to at these J. S. Lindgren J.Å. Samuelsson B. Proc. Natl. Acad. Sci. U. S. A. 1981; PubMed Scopus Google and in M. M. A. N. M. J. Biol. PubMed Scopus Google Scholar). Similar observations of the activity of LTB4 have been reported and A.W. Rev. Immunol. 1990; Google Scholar), but all that the of LTB4 by EC could be an important during the of by an of this Although we have not identified a of that activates LTA-H in intact EC, we are that a for the of Claesson and H.-E. J. J. Biochem. 1988; 173: PubMed Scopus Google that this enzyme in an active we LTA-H purified from EC by with protein This led to on possible mechanisms by which EC LTA-H. In EC, under basal we find that LTA-H is phosphorylated and that this LTA-H conversion of LTA4 to does not the activity of the enzyme. In studies, LTA-H purified from endothelial cell the lack of enzyme activity in intact of purified endothelial cell LTA-H with a protein activity to the for a of LTA-H. kinases are ubiquitous and in many We find that LTA-H is a substrate for more kinase found in the of at cell a human lung carcinoma cell line, and EA.hy an endothelial hybridoma line from the fusion of A549 with the phosphorylation in these at and it is the EC kinase that LTA-H activity. In A549 cells contain active LTA-H, suggesting that the LTA-H kinase is This may for the in activity of this enzyme in is the kinase in EC that phosphorylates to that this enzyme is not a kinase and that it may be a previously enzyme. by the of peptide it is that the EC LTA-H kinase is not of the of protein kinase C. this the kinase identified in A549 is of these it phosphorylates the LTA-H at the site as protein kinase C. and S. J. In LTA-H kinase is at °C for and is not This to the protein kinase as We have that LTA-H is not a substrate for and LTA-H is phosphorylated by kinase and the a and have on LTA-H activity. D. H. and S. J. the at which the LTA-H is phosphorylated does not with kinase Although this is we are with to the EC kinase under the that it is a protein by site-directed mutagenesis, we have identified the site at which the EC LTA-H kinase phosphorylates and the enzyme. The of serine 415 to does to the activity of the it is not what if this may play in the of epoxide the LTA-H is not a substrate for the EC LTA-H and activity is not by incubation with the cell under conditions to result in phosphorylation and of the We have of of LTA-H in the studies in this and phosphorylation conditions yield a that of of enzyme. In a number of we have that the of LTB4 synthesis with a of the of It that are at for the of in these studies of a at that This result is by the action of a protein in the kinase This is further by studies with a more purified kinase from EC to phosphorylate but not These studies have a of it is from the protein that the phosphorylation site is the of the enzyme. protein phosphatase-1 not from LTA-H. The is active in the presence of the substrate This result that the presence of a protein in the cell is to the LTA-H, but a (i.e. the presence of is The of the phosphorylation site from the action of that this site may be from the LTA-H This may of of recombinant enzyme phosphorylated by cell The EC on the other may be phosphorylated as a protein and thus be in an These that mechanism to LTA-H in endothelial cells and in other tissues as on we believe that LTA-H is regulated by phosphorylation by a LTA-H We and Dr. for critical on a of this The a of Dr. Shimizu of the of
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