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Insulin Inhibits the Expression of Intercellular Adhesion Molecule-1 by Human Aortic Endothelial Cells through Stimulation of Nitric Oxide¹

Division of Endocrinology, Diabetes, and Metabolism, State University of New York, Buffalo, New York 14209; and Kaleida Health, Buffalo, New York 14209

Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Ph.D., Diabetes-Endocrinology Center of Western New York, State University of New York, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}mfhs.edu

	Abstract

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Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelial and other cell types and participates in inflammation and atherosclerosis. It serves as a ligand for leukocyte function-associated antigen-1 on leukocytes and is partially responsible for the adhesion of lymphocytes, granulocytes, and monocytes to cytokine-stimulated endothelial cells and the subsequent transendothelial migration. Its expression on endothelial cells is increased in inflammation and atherosclerosis. As it has been suggested that insulin and hyperinsulinemia may have a role in atherogenesis, we have now investigated whether insulin has an effect on the expression of ICAM-1 on human aortic endothelial cells (HAEC). HAEC were prepared from human aortas by collagenase digestion and were grown in culture. Insulin (100 and 1000 µU/mL) caused a decrease in the expression of ICAM-1 (messenger ribonucleic acid and protein) by these cells in a dose-dependent manner after incubation for 2 days. This decrease was associated with a concomitant increase in endothelial nitric oxide synthase (NOS) expression also induced by insulin. To examine whether the insulin-induced inhibition of ICAM-1 was mediated by nitric oxide (NO) from increased endothelial NOS, HAEC were treated with N-nitro-L-arginine, a NOS inhibitor. N-Nitro-L-arginine inhibited the insulin-induced decrease in ICAM-1 expression in HAEC at the messenger ribonucleic acid and protein levels. Thus, the inhibitory effect of insulin on ICAM-1 expression is mediated by NO. We conclude that insulin reduces the expression of the proinflammatory adhesion molecule ICAM-1 through an increase in the expression of NOS and NO generation and that insulin may have a potential antiinflammatory and antiatherosclerotic effect rather than a proatherosclerotic effect.

	Introduction

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THE ASSOCIATION of hyperinsulinemia with increased coronary events in several epidemiological studies led to the hypothesis that insulin may be atherogenic (1, 2, 3). However, the epidemiological association of hyperinsulinemia with atherosclerosis has several shortcomings. Firstly, it does not establish a causal relationship between hyperinsulinemia and atherosclerosis. Secondly, this association has not been established for women in various studies. It is possible that although insulin resistance contributes to the pathogenesis of atherosclerosis, the role of hyperinsulinemia needs further investigation in this regard.

It has recently been shown that insulin is an arterial and venous vasodilator (4, 5, 6, 7). It stimulates the release of nitric oxide (NO) from human umbilical endothelial cells (8), and we have also demonstrated that insulin increases the expression of endothelial nitric oxide synthase (e-NOS) by human aortic endothelial cells (HAEC) (9), the enzyme that synthesizes NO (10). The acute release of NO induced by insulin and the increase in e-NOS expression over a longer period are consistent with the vasodilatory effect of insulin. As NO is believed to be antiatherogenic (11, 12, 13), and its inhibitor, N^G-monomethyl-L-arginine (L-NMMA), may be proatherogenic in experimental animals (14), it is likely that insulin may also have an antiatherogenic role. If so, it may reduce the expression of intercellular adhesion molecule-1 (ICAM-1), the adhesion molecule whose plasma concentrations have been shown to be related to future coronary heart disease events (15, 16, 17). ICAM-1 is constitutively expressed by endothelial cells, and its expression increases during inflammation and after endotoxin challenge (18, 19, 20).

In view of the above, we have investigated this concept further to examine the possibility that insulin may inhibit the expression of ICAM-1 in endothelial cells. Leukocyte function-associated antigen-1, the ligand of ICAM-1, is found in circulating monocytes. The binding of this ligand to ICAM-1 on endothelial cells allows monocytes to adhere to these cells, leading to the initiation of the atherogenic process on the endothelial surface (21, 22, 23). Thus, the expression of ICAM-1 on the endothelial surface may be an important determinant of potential atherogenicity in a patient. This report describes the inhibitory effect of insulin on ICAM-1 expression in HAEC through a NO pathway-mediated mechanism.

	Materials and Methods

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Cell isolation and harvesting

Human endothelial cells were harvested from human aortas and arterial vessels by the method described by Gospodarowicz et al. (24). The vessels were washed several times with phosphate-buffered saline (PBS) and incubated with 0.1% collagenase/dispase solution (Roche Molecular Biochemicals, Indianapolis, IN) in medium 199 (Life Technologies, Inc., Grand Island, NY) for 20 min. The solution was spun, and the cells were collected and harvested in flasks coated with FBS. The identity of the cells was confirmed by immunohistochemical staining, which was positive for factor VIII, Ulex europaeous, EN4, CD31, and negative for -actin. All experiments were performed using cultures at a passage of 5–6. HAEC were allowed to reach 90% confluence and then cells were washed with PBS and taken to endothelial cell growth medium (Clonetics, Walkersville, MD) containing 2% charcoal/dextran-stripped FBS (HyClone Laboratories, Inc., Logan, UT) for 24 h. On the second day, the cells were induced with insulin (0, 100, and 1000 µU/mL) and incubated for 2 days with or without N-nitro-L-arginine (L-NNA; Sigma-Aldrich Corp., St. Louis, MO).

Western blotting

Total cell lysates were prepared by washing the adherent cells with PBS followed by 1 mL boiling lysis buffer (1% SDS, 1 mmol/L sodium orthovanadate, and 10 mmol/L Tris, pH 7.4). Cells were scraped and transferred to a microcentrifuge tube, boiled for an additional 5 min, and centrifuged at 14,000 x g for 5 min. Total protein concentrations were determined using bicinchoninic acid protein assay (Pierce Chemical Co., Rockford, IL). Twenty micrograms of total cell lysate were electrophoresed on 6% SDS-polyacrylamide gels. Proteins were transferred to polyvinylidene difluoride membrane. The membrane was blocked for 1 h in 5% nonfat dry milk in 0.02% Tween/Tris-buffered saline buffer and then incubated overnight with a monoclonal antibody against e-NOS (Transduction Laboratories, Inc., Lexington, KY). The membrane was washed four times for 15 min each time with 0.02% Tween/Tris-buffered saline buffer and then incubated with peroxidase-conjugated goat antimouse Ig for 1 h. Finally, the membrane was washed and developed using supersignal chemiluminescence reagent (Pierce Chemical Co.).

ICAM-1 RT-PCR

Total ribonucleic acid (RNA) was extracted from HAEC by a single step guanidium thiocyanate-phenol-chloroform extraction method. Total RNA was treated with deoxyribonuclease I (50 U). Complementary DNA was synthesized by RT using a RETROscript first strand synthesis kit for RT-PCR (Ambion, Inc., Austin, TX). Takara human ß-actin competitive PCR (Takara, Inc., Japan) was used to correct the RNA amount for PCR among the samples. Quantum RNA 18S internal standard (Ambion, Inc., Austin, TX) or 40S ribosomal RNA S9 was used in the relative PCR as housekeeping genes. PCR primers for ICAM-1 were purchased from CLONTECH Laboratories, Inc. (Palo Alto, CA). PCR was performed in a final volume of 25 µL by adding 17.65 µL deionized H₂O, 2.5 µL 10 x PCR buffer, 1.25 µL deoxy-NTP (2.5 mmol/L), 1 µL ICAM-1 primers, 2.5 µL complementary DNA, and 0.1 µL SuperTaq polymerase (Ambion, Inc.). Two-stage thermal cycling was performed (94 C for 30 s, 68 C for 2 min). The optimal number of cycles for ICAM-1 was determined, and PCR reactions were then run under denaturing conditions on 5% polyacrylamide/8 mol/L urea ready-made gels (Bio-Rad Laboratories, Inc., Hercules, CA). Gels were then fixed and stained with silver staining using Bio-Rad Laboratories, Inc., Silver Staining Plus kit.

ICAM-1 protein levels

ICAM-1 protein levels were measured by an enzyme-linked immunosorbent assay kit obtained from R&D Systems, Inc. (Minneapolis, MN). Samples were homogenized in 0.5 mL homogenization buffer [10 mmol/L Tris-HCl (pH 7.4), 1 mmol/L ethylenediamine tetraacetate, 0.05% sodium azide, 1% Tween-80, 150 mmol/L NaCl, 2 mmol/L phenylmethylsulfonylfluoride, 1 µg/mL leupeptin, 1 µg/mL pepstatin A, and 1 µg/mL aprotinin] and analyzed according to kit procedure.

Statistical analysis

Statistical analysis was carried out using SigmaStat software (Jandel Scientific, San Rafael, CA). Paired t test was used to compare the levels of e-NOS and ICAM-1 in HAEC control cells (0 µU/mL insulin) vs. those in insulin-induced HAEC (100 and 1000 µU/mL insulin with or without L-NNA).

	Results

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HAEC homogenates from cells induced with 0, 100, and 1000 µU/mL insulin showed a dose-dependent increase in e-NOS after incubation with insulin for 2 days, as measured by Western blotting (Fig. 1, A and B). ICAM-1 gene expression as measured by RT-PCR was inhibited by insulin significantly after incubation for 2 days (Fig. 2). The concentration at which insulin inhibited ICAM-1 on the messenger RNA (mRNA) level was 100 µU/mL in some experiments and 1000 µU/mL in others. The histogram, based on densitometric readings, shows the means of four experiments, indicating that the inhibition was dose dependent, with a threshold at 100 µU/mL (Fig. 3). Treatment of HAEC with L-NNA inhibited the inhibitory effect of insulin on ICAM-1 gene expression (Fig. 3, A and B). This indicates that the inhibitory effect of insulin on ICAM-1 gene expression is mediated through the NO pathway. L-NNA did not alter basal ICAM-1 expression in HAEC in the absence of insulin.

View larger version (34K): [in this window] [in a new window]   Figure 1. A, A representative Western blot showing the induction of e-NOS in HAEC by insulin. Cells were induced with 0, 100, and 1000 µU/mL insulin for 2 days (P < 0.05). EC is the HAEC positive control for e-NOS (PharMingen/Transduction Laboratories, San Diego, CA). B, Densitometric quantitation of e-NOS expression in HAEC.

View larger version (50K): [in this window] [in a new window]   Figure 2. A, RT-PCR of ICAM-1 using 28 cycles. ICAM-1 was amplified using specific primers that produce a PCR product of 379 bp. 18S ribosomal RNA PCR products have a size of 488. The graph shows two sets of experiments. B, Densitometry of ICAM-1 RT-PCR.

View larger version (36K): [in this window] [in a new window]   Figure 3. A, RT-PCR of ICAM-1. 40S ribosomal RNA S9 was used as a housekeeping gene. It was amplified using specific primers that give a PCR product of 430 bp. L-NNA (0.25 mmol/L) was used to inhibit insulin inhibitory effect (P < 0.05). Results show clearly that ICAM-1 mRNA levels are inhibited by insulin, and the addition of L-NNA reverted ICAM-1 mRNA levels to baseline levels. HAEC were incubated with insulin and L-NNA for 2 days. B, Percent change in mRNA levels of ICAM-1, as measured by densitometry.

View larger version (36K): [in this window] [in a new window]   Figure 4. ICAM-1 protein levels 0.25 mmol/L L-NNA and 0.5 mmol/L L-NNA were used to inhibit the insulin inhibitory effect on ICAM-1 protein levels. Cells were incubated with L-NNA and insulin for 2 days.

	Discussion

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ICAM-1 is an adhesion molecule of the Ig family and is expressed on the endothelial cell surface. Its ligand, leukocyte function-associated antigen-1, which is expressed on the monocyte membrane, allows the monocyte to adhere to the endothelial cell surface to initiate the inflammatory and atherogenic processes. Increased expression of ICAM-1 is induced by endotoxin in vitro and in vivo (25, 26); an increase in ICAM-1 on the endothelial cell surface is also induced by tumor necrosis factor- (TNF) (27). ICAM-1 is a marker for inflammation and atherosclerosis; its increased levels have been shown to predict coronary events (15, 16, 17). Thus, ICAM-1 is both a mediator of inflammation and atherosclerosis as well as a marker for atherosclerosis-related clinical events.

The inhibitory effect of insulin on ICAM-1 expression allied with its potent vasodilatory effect (4, 5, 6, 7) and antiplatelet effect (28) are potentially antiatherogenic. Furthermore, some of these effects appear to be mediated through NO release. NO, too, is considered antiatherogenic (12, 13, 14), and its inhibition by L-NNA leads to a proinflammatory and proatherogenic state in the vessel wall (14). These observations support the concept that insulin is probably an unlikely mediator of atherosclerosis in insulin-resistant states. We have to look for another mediator of atherosclerosis in insulin resistance states; TNF may be one such putative molecule, as it is increased in insulin-resistant states (29, 30) and may actually antagonize insulin action at the adipocyte (31) and endothelial cell (32) levels. Indeed, TNF has been shown to increase ICAM-1 expression and to decrease NOS expression in HAEC (27, 33). TNF is also an established mediator of the acute inflammation that follows endotoxin injection (34).

In conclusion, insulin inhibits the expression of ICAM-1 markedly in HAEC. This inhibition is probably mediated by increased NO release and NOS expression, as it is inhibited by a NOS inhibitor. This effect of insulin is suggestive of an antiinflammatory action of this hormone. This effect of insulin along with its vasodilatory and antiplatelet effects militate against a proatherogenic role for insulin.

	Footnotes

 
¹ Supported by The William G. McGowan Charitable Fund, Inc.

Received February 9, 2000.

Revised March 30, 2000.

Accepted April 1, 2000.

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