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Ann Thorac Surg 1999;67:1227-1231
© 1999 The Society of Thoracic Surgeons

Original Articles

The NF{kappa}B inhibitory peptide, I{kappa}B{alpha}, prevents human vascular smooth muscle proliferation

Craig H. Selzman, MDa, Brian D. Shames, MDa, Robert C. McIntyre, Jr, MDa, Anirban Banerjee, PhDa, Alden H. Harken, MDa

a Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA

Address reprint requests to Dr Selzman, Dept of Surgery, University of Colorado Health Sciences Center, Campus Box C-320, 4200 East Ninth Ave, Denver, CO 80262
e-mail: craig.selzman{at}UCHSC.edu

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, January 25–27, 1999.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Vessel injury results in an inflammatory response characterized by the elaboration of cytokines and growth factors, which ultimately influence vascular smooth muscle cell (VSMC) growth and contribute to atherogenesis. Nuclear factor-kappa B (NF{kappa}B) is a central transcription factor important in mediating stress and inflammatory-induced signals. We hypothesized that strategies aimed at inhibiting NF{kappa}B would abrogate mitogen-induced human VSMC proliferation.

Methods. Human aortic VSMC were stimulated with basic fibroblast growth factor (FGF) and tumor necrosis factor-{alpha} (TNF), and proliferation was quantified by a colormetric assay. The influence of NF{kappa}B on VSMC proliferation was examined by both nonspecific NF{kappa}B blockade with calpain inhibitor-1 (CI-1) and dexamethasone (Dex) and specific NF{kappa}B blockade with liposomal delivery of the NF{kappa}B inhibitory peptide, I{kappa}B{alpha}.

Results. FGF and TNF induced concentration-dependent VSMC proliferation (p < 0.002). Neither CI-1, Dex, nor liposomal I{kappa}B{alpha} influenced proliferation of unstimulated VSMC. However, both FGF- and TNF-stimulated VSMC proliferation was inhibited to the level of control with CI-1, Dex, and liposomal I{kappa}B{alpha} (p < 0.001).

Conclusion. The mitogenic effect of FGF and TNF on human arterial VSMC may be prevented by inhibiting NF{kappa}B. Furthermore, liposomal delivery of endogenous inhibitory proteins such as I{kappa}B{alpha} may represent a novel, therapeutically accessible method for selective transcriptional suppression in the response to vascular injury.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Vascular smooth muscle proliferation and migration are fundamental features of intimal hyperplasia and atherogenesis. In response to vascular injury, growth factors and cytokines are released from T-lymphocytes, platelets, macrophages, endothelial cells, and vascular smooth muscle cells (VSMC) themselves. These peptides may influence VSMC phenotype and growth, ultimately promoting the development of advanced fibroproliferative lesions [1]. Nuclear factor kappa B (NF{kappa}B) is a transcription factor that acts as a central intracellular mediator of stress and inflammatory signals [2]. NF{kappa}B is upregulated in atherosclerotic lesions [3] and is activated in several atherogenic situations including balloon injury, shear stress, and exposure to oxidized low density lipoprotein (LDL), platelet-derived growth factor, basic fibroblast growth factor (FGF), and tumor necrosis factor-{alpha} (TNF) [4–6]. NF{kappa}B is often viewed as a global regulator of cytokines that promotes gene transcription of mitogenic products including TNF, interleukins-1ß, -2, -6, and -8, as well as adhesion molecules, acute phase proteins, immunoreceptors, and TNF itself [2]. Additionally, accumulating evidence suggests that NF{kappa}B has an important role in the signals that control VSMC function both in vitro as well as in atherosclerotic VSMC in vivo [7, 8].

The NF{kappa}B family of proteins is characterized by the Rel homology domain, which is conserved in its five members: c-Rel, NF{kappa}B1 (p50/p105), NF{kappa}B2 (p52/p100), Rel-A (p65), and Rel-B. When bound by its inhibitory protein, I{kappa}B{alpha}, classic NF{kappa}B (p65/p50) exists in the cytoplasm as an inactive dimer. Upon stimulation, phosphorylation of I{kappa}B{alpha} identifies it for ubiquitination and subsequent degradation by the proteasome. Released from the NF{kappa}B:I{kappa}B{alpha} complex, NF{kappa}B is free to translocate to the nucleus, engage DNA, and initiate gene transcription. Once activated, NF{kappa}B promotes the production of I{kappa}B{alpha} itself, thus creating an inducible autoregulatory system. Because of it central role as a "brake" for NF{kappa}B translocation, manipulation of I{kappa}B{alpha} levels represents an attractive strategy for modifying NF{kappa}B activity. Within the paradigm linking inflammation to atherogenesis, we hypothesized that inhibiting NF{kappa}B activity would abrogate human VSMC proliferation. The purposes of the present study were to: (1) determine the influence of FGF and TNF on human VSMC proliferation in vitro; and (2) examine the effect of both specific and nonspecific NF{kappa}B blockade on the VSMC mitogenic response to these prototypical atherogenic mediators.


   Material and methods
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 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Materials
Dulbecco’s modified Eagle’s media (DMEM) and dexamethasone were obtained from Sigma Chemical Co. (St. Louis, MO). L-Glutamine (200 mM), trypsin-EDTA (0.05%), and antibiotic/antimycotic (penicillin G, 10,000 Units/mL, streptomycin sulfate, 10,000 mg/mL; amphotericin, 25 mg/mL) were obtained from Gibco Brl (Grand Island, NY). Fetal bovine serum (FBS) was obtained from Summit Biotechnology (Fort Collins, CO). Human cord serum was graciously provided by Dr Lawrence Horwitz (University of Colorado, Denver, CO). Human TNF and FGF were obtained from R&D Systems (Minneapolis, MN). I{kappa}B{alpha}-glutathionine-S-transferase (GST) fusion protein was obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Calpain inhibitor-1 was obtained from Calbiochem (La Jolla, CA).

Cell culture and proliferation assay
Human VSMC were isolated from segments of thoracic aortae harvested from transplant donors as previously described [9]. VSMC were trypsinized and plated at a density of 2,500 cells/well on 1% gelatin-coated 96-well microtiter plates with a "complete media" containing DMEM, 5% each of FBS and human cord serum, and antibiotic/antimycotic. After 8 h, the media were removed and replaced with serum-free media for 48 h to allow for growth arrest. Twenty-four hours after the substitution of media with the experimental agent, rates of proliferation were determined using the CellTiter 96 assay (Promega, Madison, WI). We have previously demonstrated that this technique is equivalent to direct VSMC counting in determining viable cell numbers [10]. After the addition of 20 µL of a methyltetrazolium salt compound, plates were incubated at 37°C for 90 min. Absorbance was then recorded at 490 nm with a microtiter plate reader (Bio-Rad, Hercules, CA). Results, reported as optical densities, represent experiments done in quadruplicate from two separate donors during passages 1–4.

Liposome preparation
Liposomal delivery of recombinant I{kappa}B{alpha}-GST fusion protein was performed as a modification of a previously described technique [11]. A lipid solution composed of 2.0 mg egg L-{alpha}-phosphatidylcholine, 0.5 mg of cholesterol, 0.5 mg of 1,2-dioleoyl-3-trimethyl ammonium-propane, and 0.5 mg of dioleoyl phosphatidylethanolamine (Avanti Polar-Lipids, Alabaster, AL) was dissolved in chloroform and dried in a chloroform-pretreated 12 x 75-mm glass tube by rotation in a vacuum. I{kappa}B{alpha}-GST fusion protein was dissolved (50 µg) in 100 µL of 50 mM Tris-HCl (pH 7.5) and was added to the dried lipids and agitated by alternate cycles of sonication (10 sec) and vortex (20 sec). Liposomes containing the GST moiety alone were prepared in a similar manner, but I{kappa}B{alpha}-GST fusion protein was substituted with an equimolar concentration of recombinant GST. Control liposomes contained 100 µL of 50 mM Tris-HCl buffer. The liposome mixture was extruded for 20 passes through a 0.1-mm membrane with the aid of an ethanol-pretreated extrusion device (Avestin, Ottawa, ON) and mixed with DMEM/5% FBS medium.

Statistical analysis
Data are presented as mean values ± the standard error of the mean. Analysis of variance (ANOVA) with Bonferroni-Dunn post hoc analysis was used to analyze differences between experimental groups. Statistical significance was accepted within 95% confidence limits.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Influence of TNF and FGF on human VSMC proliferation
Human aortic VSMCs were stimulated with either FGF or TNF for 24 h. Both mitogens induced concentration-dependent human VSMC growth (Fig 1). Compared with control, FGF induced VSMC proliferation in doses as low as 100 pg/mL (0.646 ± 0.026 vs 0.422 ± 0.052, p < 0.002). Maximal FGF stimulation was observed at 10 ng/mL (0.729 ± 0.025, p < 0.002 vs control). Similarly, compared with control, TNF induced VSMC proliferation in doses as low as 100 pg/mL (0.667 ± 0.088 vs 0.422 ± 0.052, p < 0.002). Maximal TNF stimulation was observed at 10 ng/mL (0.807 ± 0.028, p < 0.002 vs control). Based on these results, a dose of 10 ng/mL of FGF and TNF was used in subsequent experiments.



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  		Fig 1. Growth factor and cytokine-induced vascular smooth muscle proliferation. VSMCs were incubated in control media (Cont) or increasing concentrations of FGF (A) or TNF (B) for 24 h. Both FGF and TNF induced concentration-dependent VSMC (*p < 0.002 versus control).

 
Influence of nonspecific NF{kappa}B blockade on human VSMC proliferation
To determine the role of NF{kappa}B in mitogen-induced VSMC proliferation, we examined whether maintaining levels of its inhibitory protein, I{kappa}B{alpha}, could inhibit VSMC proliferation. To investigate this question, we sought to determine the influence of two NF{kappa}B inhibitors with distinct mechanisms of action, calpain inhibitor-1 (CI-1) and dexamethasone (Dex). CI-1 prevents induced proteolysis of I{kappa}B{alpha}, and glucocorticoids induce synthesis of I{kappa}B{alpha}, thus binding free cytosolic and nuclear NF{kappa}B [12, 13]. Ultimately, both prevent the release of active NF{kappa}B and inhibit NF{kappa}B-dependent gene transcription.

When incubated for 24 h with VSMC, neither calpain inhibitor-1 (100 µg/mL) nor dexamethasone (1 µM) influenced VSMC proliferation compared with control (Fig 2). However, when concomitantly stimulated with either FGF (10 ng/mL) or TNF (10 ng/mL), both inhibitors attenuated the VSMC mitogenic response (Fig 3). Calpain inhibitor-1 reduced FGF-induced and TNF-induced VSMC proliferation by 35% and 49%, respectively (p < 0.001). Similarly, dexamethasone reduced FGF-induced and TNF-induced VSMC proliferation by 22% and 45%, respectively (p < 0.001). Importantly, VSMC remained greater than 95% viable by trypan blue exclusion.



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  		Fig 2. Influence of nonspecific and specific NF{kappa}B blockade on unstimulated VSMC growth. Dexamethasone (Dex), calpain inhibitor-1 (CI-1), liposomes containing the GST moiety alone (Lipo), and liposomal I{kappa}B{alpha} (I{kappa}B{alpha}) had no effect on unstimulated VSMC proliferation.

 


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  		Fig 3. Influence of nonspecific NF{kappa}B inhibition on mitogen-stimulated VSMC. FGF (10 ng/mL) and TNF (10 ng/mL) induced VSMC proliferation compared with control ({dagger}p < 0.001). Both dexamethasone (Dex) and calpain inhibitor-1 (CI-1) inhibit FGF- and TNF-induced VSMC proliferation (*p < 0.001, versus [A] FGF and [B] TNF).

 
Influence of liposomal I{kappa}B{alpha} on human VSMC proliferation
Calpain inhibitors and glucocorticoids are nonspecific inhibitors of NF{kappa}B activation. They may act to effect proteolysis and signaling of several other transduction intermediates, not just I{kappa}B{alpha}. Therefore, we sought to elevate levels of I{kappa}B{alpha} by direct delivery of the recombinant protein. Preliminary experiments using VSMC proliferation and cell necrosis as outcome variables demonstrated that the optimal dose of purified I{kappa}B{alpha} was a final concentration of 20 µg/mL, and as such, this concentration was used for all ensuing experiments (data not shown). The commercially available I{kappa}B{alpha} peptide is bound to a GST moiety. Several experiments demonstrated that neither empty liposomes, liposomes containing recombinant GST alone, nor liposomes with I{kappa}B{alpha} influenced unstimulated VSMC proliferation (Fig 2). Conversely, incubation of liposomal I{kappa}B{alpha} with stimulated VSMC reduced FGF-induced and TNF-induced VSMC proliferation by 51% and 65%, respectively (p < 0.001). Stimulated VSMC treated with liposomal I{kappa}B{alpha} remained greater than 95% viable by trypan blue exclusion. Importantly, concurrent treatment of stimulated cells with liposomes containing only the GST moiety did not effect FGF- or TNF-induced VSMC proliferation (Fig 4).



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  		Fig 4. Influence of specific NF{kappa}B blockade with liposomal delivery of I{kappa}B{alpha} on mitogen-stimulated VSMC. Both FGF (10 ng/mL) and TNF (10 ng/mL) induced VSMC proliferation compared with control ({dagger}p < 0.001). Simultaneous incubation with liposome containing the GST moiety alone (Lipo) had no effect on FGF- or TNF-induced proliferation. Liposomal delivery of I{kappa}B{alpha} (I{kappa}B{alpha}) inhibited both FGF- and TNF-stimulated VSMC proliferation (*p < 0.001, versus [A] FGF and [B] TNF).

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
After vascular injury, cytokines and growth factors act to modify the vessel wall. We acknowledge that a wide array of inflammatory mediators are implicated in atherogenesis, and no single cytokine or growth factor is likely responsible for the events associated with vascular remodeling. FGF, as a representative of the growth factor family, and TNF, as a representative of the cytokine family, are both released from a variety of inflammatory cells, and their expression is upregulated in atherosclerotic lesions. Our results demonstrate that both FGF and TNF stimulate human VSMC proliferation (Fig 1). TNF and FGF stimulate cellular proliferation through distinct ligand-receptor interactions. The mechanism of TNF-induced VSMC proliferation is unknown. Some evidence suggests that while the TNF p55 receptor appears to direct apoptosis, the TNF p75 receptor likely promotes cellular proliferation through the mitogen-activated protein kinase system [14]. FGF promotes VSMC proliferation through receptor tyrosine kinase pathways to modify gene transcription, translation, and cell cycle progression [15]. Quite possibly, cytokine and growth factor signals may converge at distal signaling points to conspire in promoting VSMC proliferation.

Accumulating evidence suggests that NF{kappa}B activation represents a central and essential step for engaging the proliferative machinery of a cell. Yet, while investigators have reported both FGF- and TNF-induced NF{kappa}B DNA binding activity in VSMC [5, 8], few have mechanistically linked this activation with cellular proliferation. Several experimental approaches have been implemented to inhibit NF{kappa}B activity, including transdominant I{kappa}B{alpha} mutants, antisense p65 oligonucleotides, microinjection of I{kappa}B{alpha}, protease inhibitors, and antiinflammatory and immunosuppressive drugs [16]. Bellas and colleagues used antioxidants and pentoxifylline, as well as in vitro microinjection of I{kappa}B{alpha}, to demonstrate NF{kappa}B-dependent proliferation in serum stimulated bovine aortic VSMC [17]. However, these strategies of NF{kappa}B blockade are limited by their nonspecific effects or clinical inaccessibility. Other investigators have utilized antisense p65 oligonucleotides to inhibit NF{kappa}B in serum- [18] and thrombin- [19] induced VSMC proliferation. A potential mechanistic pitfall to antisense technology is that human VSMC NF{kappa}B activity is mediated by p65/p50 heterodimers. Isolated p65 antisense message or NF{kappa}B-3' decoys only address a single element of the NF{kappa}B complex. Moreover, attempts to chronically inhibit NF{kappa}B with NF{kappa}B knockouts or over-expression of I{kappa}B{alpha} implicitly carry the danger of compensatory adaptation. As such, therapeutic and mechanistic linking of mitogenic responses to NF{kappa}B activity can be problematic.

Although dexamethasone and calpain inhibitors act to stabilize the NF{kappa}B:I{kappa}B{alpha} complex, prevent NF{kappa}B activation, and inhibit mitogen-induced VSMC proliferation, both are nonspecific inhibitors and may influence other intracellular events. Therefore, direct delivery of the specific natural inhibitor, I{kappa}B{alpha}, is an engaging strategy. Currently, there are six known members of the I{kappa}B family ({alpha}, ß, {gamma}, {delta}, {epsilon}, and Bcl-3). The present study focuses on I{kappa}B{alpha}, but the relative importance of the different isoforms of I{kappa}B in coordinating NF{kappa}B activity remains uncertain. The interaction between I{kappa}B{alpha} and NF{kappa}B is, however, the best understood of the isoforms. Cationic liposomes have typically been utilized as a method to introduce DNA intracellularly. Few studies have demonstrated successful delivery of polypeptide proteins by liposomes. Several different liposomal preparations exist. Recently, Scott-Burden and colleagues reported that in rat and bovine aortic VSMC, liposomes alone stimulated inducible nitric oxide synthase expression [20]. Nonspecific lipid effects and nitric oxide production by the liposomal preparation are potentially troublesome as they may alter VSMC proliferation itself. In the present study, the empty liposomal preparation, as well as the liposome with recombinant GST moiety alone, had no effect on VSMC proliferation. These results suggest that the empty submicron liposome preparations used in the present study lack detectable independent biologic activity in our model of human VSMC proliferation.

Although we demonstrate that NF{kappa}B activation is essential for mitogen-induced VSMC proliferation, the mechanism of NF{kappa}B-driven VSMC proliferation remains speculative. On one hand, evidence suggests that NF{kappa}B can suppress apoptosis in several cell lines [21]. As such, activation of NF{kappa}B provides a survival pathway that may balance signals in favor of cell growth. Alternatively, NF{kappa}B activation promotes production of several well-known mitogens, including platelet-derived growth factor (PDGF), IL-1ß, IL-6, IL-8, and TNF [22]. Finally, the ability of NF{kappa}B to intervene in the cell cycle machinery remains unknown. Within the inflammatory paradigm of atherogenesis, we show that mitogen-induced human VSMC proliferation is inhibited by strategies aimed at preventing NF{kappa}B activation. In particular, we demonstrate that purified I{kappa}B{alpha} may be directly delivered to VSMC by liposomes and prevent VSMC proliferation. Direct administration of native inhibitory proteins, such as I{kappa}B{alpha}, may offer a novel, clinically accessible method of selective transcriptional regulation over signaling events important in the response to vascular injury.


   Footnotes
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Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 
This work was supported in part by grants from the National Institutes of Health: GM-08315 (CHS), GM-49222 (AHH), and the Pacific Vascular Research Foundation (CHS).


   References
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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