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Development and Characterization of Essential Fatty Acid Deficiency In Proc. Natl. Acad. Sci. USA Vol. 92, pp. 1147-1151, February 1995 Cell Biology Development and characterization of essential fatty acid deficiency in human endothelial cells in culture (eicosapentaenoic acid/prostacycline) RICHARD LERNER*t, PETER LINDSTR6M*, ANDERS BERGt, ELSBETH JOHANSSONt, KERSTIN ROSENDAHLt, AND JAN PALMBLAD* Departments of *Medicine and tClinical Chemistry, Karolinska Institute, Stockholm Soder Hospital, S-118 83 Stockholm, Sweden Communicated by Ralph T. Holman, University of Minnesota, Austin, MN, September 19, 1994 (received for review September 8, 1993) ABSTRACT We induced an essential fatty acid deficiency Against this background we asked whether functional re- (EFAD) in human umbilical vein endothelial cells by culture sponses of endothelial cells, being intimately involved in the in medium with 20% (vol/vol) delipidated fetal calf serum. inflammatory reaction, might be reduced in EFAD. This EFAD, reflected by decreased cellular linoleic acid (18:2co6) report concerns the biochemical characterization of EFAD and arachidonic acid (20:4o6) and emergence ofthe oleic acid produced in human umbilical vein endothelial cells (HUVEC) derivative 5,8,11-eicosatrienoic acid (20:3to9; Mead's acid), by culturing the cells in a delipidated medium, the generation was evident after 1 week of culture and became pronounced of prostacycline (PGI2), and the ability to respond with a rise after 2 weeks. Beyond that time point, control cells (cultured of cytosolic concentrations of Ca2 , [Ca2+] . in 20% normal fetal calf serum) grew deficient of 18:2w6, and EFAD cells died. 18:2co6 addition to EFAD cells resulted in MATERIALS AND METHODS dose-dependent increases of 18:2o6 and 20:4o6. 20:4w6 or 5,8,11,14,17-eicosapentaenoic acid (20:5W3) additions re- Chemicals. 20:4w6, 5,8,11,14,17-eicosapentaenoic acid sulted in normalization of these and conversion of (20:503), heparin, human serum albumin (essential fatty acid- acids, free), 18:2c6, thrombin, and Triton X-100 were obtained from 20:5W3 to 4,7,10,13,16,19-docosahexaenoic acid (22:6W3) was Sigma. Hepes, fetal calf serum (FCS), penicillin, streptomycin, noted. Agonist-induced increases in concentrations of pros- trypsin, RPMI 1640 medium, and Hanks' balanced salt solu- tacycline (prostaglandin 12; PGI2) and cytosolic Ca2+, tion (HBSS) were from GIBCO. Collagenase (type 3) was [Ca2+]1, were reduced in EFAD cells and not restored by from Worthington, and endothelial cell growth supplement 18:2to6 or 20:4w6 additions. Change of the medium in EFAD was from Collaborative Research. Fura-2 acetoxymethyl ester cultures 1 day before the experiments decreased 20:3w9 and (AM) and ionophore A23187 were from Calbiochem. Acetyl normalized the PGI2 production and [Ca2+1i changes, chloride, 1-butanol, diisopopyl ether, demthyl sulfoxide, whereas addition of 20:3o9 to control cells impaired the EDTA, methylbenzene, methyl margarate, and potassium [Ca2+]i response, indicating a suppressive effect of 20:3o9. carbonate were from Merck. 5,8,11-Eicosatrienoic acid Thus, EFAD in endothelial cells is associated with abnormal- (20:3co9; Mead's acid) was obtained from Cayman Chemicals ities of eicosanoid and second-messenger production partly (Ann Arbor, MI). attributable to 20:3o9 accumulation. Moreover, the gradual Delipidated FCS. Delipidated serum was obtained from emergence of 18:2co6 deficiency in regularly grown control FCS as described (20). Before delipidation the cholesterol cells underlines the need for careful analysis of fatty acids in content was 0.9 mmol/liter; triglycerides, 0.9 mmol/liter; and long-term cell cultures. free fatty acids, 0.09 mmol/liter. After the procedure choles- terol and triglycerides were not detectable, and the free acid Essential acid concentration was 0.02 mmol/liter. fatty deficiency (EFAD) is characterized by HUVEC. Endothelial cells were obtained from human um- growth retardation, skin and renal lesions, increased suscep- bilical veins (21, 22). Cells were resuspended in culture me- tibility to infections, and reduced autoimmune and inflamma- dium (RPMI 1640 containing 20% (vol/vol) FCS, 90 ,ug of tory reactions (1-9). EFAD is also associated with alteration heparin per ml, 50 ,ug of endothelial cell growth supplement of functional responses of neutrophil granulocytes and mac- per ml, 200 units of penicillin per ml, and 200 ,ug of strepto- rophages that is normalized when linoleic acid (9,12- mycin per ml) and were grown in tissue culture flasks. HUVEC octadecadienoic acid; 18:2X6), the major dietary essential fatty were trypsinized when confluent, counted, and equally resus- acid for mammals, is replenished (10-12). pended in standard medium or delipidated medium (20% The biochemical basis for impairment of phagocyte re- delipidated FCS), grown in flasks, and passaged every week. sponses in EFAD is assumed to be lack of eicosanoids, Photographs were taken every day, and cell growth was metabolites generated from cellular 18:2o6 and arachidonic calculated from the graphs. For the PGI2 release assay, acid (5,8,11,14-eicosatetraenoic acid; 20:4X16) and in particular HUVEC were transferred to 10-cm2 Petri dishes. Fatty acid cyclo- and lipoxygenase products. This hypothesis is supported analyses were made every week. Indirect immunofluorescence by a number of observations most importantly that develop- staining against factor VIII-related antigen was used for ment of decreased endogenous generation of leukotrienes, characterization of cells in culture. Fatty acids dissolved in prostaglandins, and platelet-activating factor coincide with impairment of cellular responsiveness (13-19). Moreover, Abbreviations: EFA, essential fatty acid(s); EFAD, EFA deficient/ addition of 18:2co6, 20:4X6, or lipoxygenase products to EFAD deficiency; [Ca2+]i, cytosolic Ca2+ concentrations; HUVEC, human cells may restore their responsiveness, including production of umbilical vein endothelial cells; PGI2, prostaglandin 12 (prostacy- eicosanoids (18, 19). cline); PGFia,, prostaglandin Fla; 18:2w6, 9,12-octadecadienoic acid (linoleic acid); 20:3w9, 5,8,11-eicosatrienoic acid (Mead's acid); 20:4w6, 5,8,11,14-eicosatetraenoic acid (arachidonic acid); 20:5c3, The publication costs of this article were defrayed in part by page charge 5,8,11,14,17-eicosapentaenoic acid; 22:6o3, 4,7,10,13,16,19-docosa- payment. This article must therefore be hereby marked "advertisement" in hexaenoic acid; FCS, fetal calf serum. accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 1147 Downloaded by guest on October 1, 2021 1148 Cell Biology: Lerner et al. Proc. Natl. Acad Sci. USA 92 (1995) Table 1. Growth of HUVEC in control and EFAD media [Ca2+], were done as described (24, 25). Results were ex- Cells, no. per mm2 pressed as the net increase of the [Ca2+]i above that of resting cells. Days in culture Control EFAD Statistical Calculations. These were carried out with Stu- 2 312 + 16 172 + 17 dent's t test. 4 581+51 297+20 6 704+32 418+18 RESULTS 8 700 + 26 427 + 19 Cell Growth and Morphology. The replication rate of Data are means ±+ SEM for three separate experiments. HUVEC grown in EFAD medium was lower than in normal ethanol were added to HUVEC cells, and the solvent at a medium (Table 1). This growth retardation was evident corresponding concentration was added to control cells. already at culture day 2 and became progressively more Fatty Acid Analysis. The direct transestrification method prominent. After 2-3 weeks of culture, EFA-deprived cells (23) was used with some modifications. Separation of fatty acid stopped growing, and cell death hampered further evalua- morphology was changed in was performed in the gas chromatograph (Finnigan-MAT, tion. The normal HUVEC EFAD cultures. After 1 week, and more prominently after 2 Sunnyvale, CA). Fatty acids were identified in a mass spec- trometer (Model 1020 Finnigan). weeks of culture, EFAD cells became more elongated and formed a less dense monolayer relative to controls. Addi- PGI2 Release. HUVEC, grown to confluence in 10-cm2 tions of 20:4X6, 18:2w6, or 20:5w3 did not restore the normal Petri dishes, were washed three times and subsequently cov- HUVEC morphology during the observation time of 3 days. ered with 1 ml of HBSS containing 10 mM Hepes. Stimuli or EFAD cells did not differ from control cells in immunoflu- HBSS alone (for assessment of spontaneous release) was orescence for factor VIII-related antigen. were incubated for 2 or 10 min, and superna- added. Dishes Cellular Fatty Acids. Relative contents of fatty acids are tants were one set aspirated. In of experiments, HBSS-treated shown in Table 2 and Figs. 1-3. In HUVEC grown in delipi- cells were lysed by adding 0.1% Triton X-100, and the resulting dated serum, reduced contents of O3 and c6 fatty acids could fluid phase was processed as the supernatants had been. All be observed after 1 week of culture and became more evident aspirates were frozen immediately. The remaining HUVEC after 2 weeks. The marker for EFAD, the oleic acid desatu- layers were lysed with distilled water, frozen and thawed ration and elongation product 20:3(09, appeared after the first repeatedly, and analyzed for total protein content with a week of culture (Fig. 2 Left). The mean ratio of 20:3(09 to Coomassie blue technique (Bio-Rad). PGI2 was assessed as its 20:4co6 increased gradually in EFAD cells but not in control stable metabolite 6-keto-PGFia by a radioimmunoassay (Am- cells. Control cells did not exhibit changes of fatty acid ersham). concentrations over the first week of culture, but reductions of [Ca2J1, Measurements. HUVEC grown on coverslips were EFA occurred to some extent during the second week. The treated with 2-4 ,uM Fura-2 AM in HBSS containing 10 mM saturated fatty acids did not differ between EFAD and control Hepes and 1% human serum albumin for 40 min (24). The cells on day 10.
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