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Cardiovascular Research 2004 61(1):11-21; doi:10.1016/j.cardiores.2003.09.033
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

The ubiquitin–proteasome system in cardiovascular diseases—a hypothesis extended

Joerg Herrmann*,a, Aaron Ciechanoverb, Lilach O Lermanc and Amir Lermana

aDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
bRappaport Institute for Research in Medical Sciences, Technion-Israel Institue of Technology, Haifa, Israel
cDivision of Hypertension, Mayo Clinic, Rochester, MN, USA

* Corresponding author. Department of Internal Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1-507-255-5890; fax: +1-507-255-1824. herrmann.joerg{at}mayo.edu

Received 22 August 2003; revised 29 September 2003; accepted 30 September 2003


   Abstract
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1. The structure of...
 2. The regulation of...
 3. The function of...
 4. The ubiquitin-proteasome...
 5. The ubiquitin-proteasome...
 6. The ubiquitin-proteasome...
 7. Therapeutic implications
 8. Summary
 References
 
During recent years, the ubiquitin–proteasome system has become known as the major pathway of non-lysosomal degradation of intracellular proteins, involving two sequential steps. In the first step, multiple moieties of ubiquitin are covalently bound to target proteins to be recognized and degraded by the multi-enzymatic proteasome complex in the second step. In addition to the elimination of damaged and unneeded proteins, this system fulfills an important function in the regulation of cellular mediators in various biological pathways. Foremost, these biological pathways include inflammation, cell proliferation, and apoptosis, all of which constitute important characteristics of atherosclerosis. Indeed, recent experimental evidence supports a potential involvement of the ubiquitin–proteasome system in the initiation, progression, and complication stage of atherogenesis. This review summarizes recent findings regarding the ubiquitin–proteasome system in cardiovascular diseases and discusses the potential use of proteasome inhibitors in cardiovascular therapy.

KEYWORDS Apoptosis; Atherosclerosis; Coronary disease; Restenosis

In the early 1970s, a polypeptide was isolated and purified from bovine thymus, capable of inducing differentiation of thymus-derived T cells and bone-marrow-derived B cells. This 8.5-kDa polypeptide was subsequently found in various cell types, hence receiving the name "ubiquitous immunopoietic polypeptide" (UBIP) [1]. The ultimate significance of this peptide was emphasized when it was discovered to be, in fact, the heat-stable polypeptide essential for the activity of the ATP-dependent proteolytic system in reticulocytes, which was henceforth called "ubiquitin" [2]. Ever since, further insight was gained into this energy-dependent system, finding it to primarily label proteins for degradation by the multi-enzymatic proteasome complex, hence coining the name "ubiquitin–proteasome system" [3,4]. In this article we review current knowledge about the structure and function of this system and extend on its hypothesized role in cardiovascular diseases [5,6].


   1. The structure of the ubiquitin–proteasome system
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Protein metabolism, pivotal for normal cellular function, involves both synthesis and degradation of proteins on a constant basis. Eukaryotic cells are equipped with three different systems to accomplish protein degradation: the mitochondrial proteases, which degrade the majority of mitochondrial proteins, the lysosomes, which degrade membrane and endocytosed proteins, and the ubiquitin–proteasome system, which degrades the vast majority of long- and short-lived normal and abnormal intracellular proteins [7]. In fact, up to 80–90% of all intracellular proteins are degraded via the ubiquitin–proteasome system, which is hence considered to be the major pathway of intracellular protein degradation and of utmost significance for cell biology.

Degradation of proteins via the ubiquitin-proteasome system involves two distinct, sequential steps [8]. In the first series of reactions, multiple moieties of ubiquitin are activated, transferred, and bound to cellular proteins by action of E1, E2, and E3 enzymes, respectively, generating a polyubiquitin chain, which sometimes requires the stabilizing action of an E4 molecule. In the second step, cellular proteins, labeled by a chain of at least four ubiquitin moieties, are recognized and degraded by the 26S proteasome complex (Fig. 1) [9,10]. Of note, the proper interaction of some proteins with the ubiquitin system or the proteasome complex necessitates the facilitating action of chaperones such as HSP70 or chaperone-like molecules such as the valosin-containing protein [11,12].


Figure 1
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  		Fig. 1 Illustration of the ubiquitin–proteasome system. The ubiquitin system comprises three sucessive steps: the activation of ubiquitin (Ub) by the formation of a thio-ester binding to E1 (Ub activating enzyme), the tranfer of Ub via E2 (Ub carrier enzyme) to E3, which covalently binds Ub to a lysine residue of the target protein either directly (RING domain E3) or via an intermediate thio-ester formation within the E3 (HECT domain E3). This process, leading to mono- or polyubiquitination, is balanced by the enzymatic process of de-ubiquitination, mediated by a number of enzymes. Whereas mono-ubiquitination exerts a modulatory effect upon protein function, poly-ubiquitination leads to protein degradation. Facilitated by the action of carrier molecules such as valosin-containing protein (VCP) in certain cases, proteins, tagged with a chain of at least four Ub molecules, bind to the recognition site on the 26S proteasome complex. The 26S proteasome complex comprises a central 20S proteolytic core, formed by four rings in barrel-shape structure, and two 19S regulatory units to either side of it. Besides their recognition function, the 19S regulatory units are mainly responsible for unfolding the substrate proteins into the direction of the 20S proteasome. Passage through this proteolytic tunnel, mainly the inner beta-rings, which harbor most of the proteolytic activity, leads to the generation of protein fragments, six to eight amino acids in length. Detachment of VCP and the Ub chain from the target protein prior to its move through the proteolytic tunel restores their intracellular pools.

 

   2. The regulation of the ubiquitin–proteasome system
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For fine-tuning of cellular function, the ubiquitin–proteasome system is regulated tightly and with a high degree of specificity [13]. This is accomplished primarily on the level of the E3 enzymes, which finalize the ubiquitination cascade by the formation of an isopeptide bond between the activated C-terminal glycine residue of ubiquitin and an amino group in epsilon position of a lysine residue of either the target protein or a previously conjugated ubiquitin moiety following association with the target protein on the basis of certain recognition patterns. One of the most important recognition patterns is a "destabilizing" (free basic, bulky hydrophic, or uncharged) N-terminal amino acid. This sequence can be a standard characteristic of a protein (primary destabilizing N-terminal amino acids, e.g. arginine and lysine) or may be generated via one (secondary destabilizing N-terminal residues such as apartate, glutamate, and cystein) or two (tertiary stabilizing N-terminal residues such as asparagine and glycine) intermediate steps. Clearly, this system relates the half-life of an intracellular protein to its N-terminal residue, which has become known as the N-end rule [14]. It also mediates degradation of proteins after their initial cleavage, for instance cohesin, which is involved in the cohesion of sister chromosomes during mitosis [15]. The overall significance of the hierarchical system of the N-end rule pathway for the development of the cardiovascular system has recently been demonstrated in the severe heart defects and the impairment of maturation of early vascular plexus occurring as a consequence of ATE-1-targeted deficiency in Arg-tRNA-protein transferases, which mediate the conjugation of arginine to the N-termini of proteins as part of the pathway [16]. Other important substrate recognition patterns for the ubiquitin–proteasome system are protein phosphorylation and hydroxylation. Proteins that undergo ubiquitin-mediated degradation following phosphorylation or hydroxylation include the inhibitory molecules to nuclear factor kappa B (I{kappa}B) and hypoxia-inducible factor 1 alpha (HIF-1{alpha}), respectively [17,18].

Recently, it was discovered that the consequences of polyubiquitination are crucially determined by the position of the ubiquitin lysine residue involved in the reaction. Whereas polyubiquitination involving the lysine residue at position 48 of the amino acid sequence of ubiquitin leads to protein degradation by the proteasome, modulation of protein function remains to be the only consequence of polyubiquitination involving the lysine residue at position 63 [19]. An intriguing example for this latter aspect is the regulation of the I{kappa}B kinase complex (IKK) by so-called K63 polyubiquitination, which seems to be additive and even complementary to IKK activation by phosphorylation [20]. In addition to K63 polyubiquitination, monoubiquitination has been described as yet another mode of functional regulation of the activity of proteins, e.g. in the metabolism of cell surface receptors [21,22].

In addition to its substrates, the activity of the ubiquitin system itself can be modulated by a number of factors, including glucocorticoids, thyroid hormones, cytokines, and cancer-expressed proteins such as proteolysis-inducing factor (PIF) [7,23]. Notably, some factors, e.g. interferon gamma (IFN{gamma}), not only stimulate the modification of substrates of the ubiquitin system, including the I{kappa}B family of proteins, but, furthermore, modify the components of the enzymatic machinery of the ubiquitin system and the proteasome complex [24–26]. Further coordination between substrates and system might be reflected by the fact that protein kinase C and tyrosine kinase pathways are not only involved in the modifcation of substrates of the ubiquitin–proteasome system but also mediate the phosphorylation of E1 and E2, thereby increasing their activities by even more than twofold [27].


   3. The function of the ubiquitin–proteasome system
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The considerable diversity of its substrates accounts for the central involvement of the ubiquitin–proteasome system in a number of physiological and pathophysiological processes, including inflammation and cell cycle control (Table 1).


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  		Table 1 Representative protein substrates of the ubiquitin–proteasome system

 
MHC class I antigen processing of antigen-presenting cells (APC) is one of the most prominent examples of the involvement of the ubiquitin–proteasome system in inflammation [28,29]. Furthermore, the ubiquitin–proteasome system plays a significant role in the regulation of both T cell receptor (TCR) and co-stimulatory CD28 signaling by virtue of the action of ubiquitin ligases of the Cbl family [30,31]. Whereas c-Cbl negatively affects TCR signaling by targeting the ZAP-70 tyrosine kinase pathway, Cbl-b exerts an inhibitory effect upon TCR-coupled signaling by interfering with the CD28-triggered activation of the PI3-kinase pathway [32–34]. As recently demonstrated, CD28 co-stimulation leads to the ubiquitination and degradation of Cbl-b, which eliminates the negative regulator and allows the expression of, for instance, IL-2 and the IL-2 receptor [35]. Still the most important link between the ubiquitin–proteasome system and inflammation relates to the transcription factor nuclear factor kappa B (NF{kappa}B). As displayed in Fig. 2, the ubiquitin–proteasome system takes center stage in the main activation pathway of NF{kappa}B, which leads to the expression of a number of inflammation-related genes [36–40].


Figure 2
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  		Fig. 2 Activation pathway of NF{kappa}B, a homo- or heterodimeric transcription factor, composed by members of the Rel family of proteins. The classical example of NF{kappa}B is the heterodimer of p50 and p65, which binds to the 5'-GGGANNYYCCC-3' consensus sequence, once released from the association with an inhibitory molecule of the I{kappa}B family, primarily I{kappa}B{alpha} and I{kappa}Bβ. I{kappa}Bs possess multiple copies of ankyrin repeat motifs, which interact with the Rel homology domain of Rel proteins, thereby masking the nuclear translocation signal and sequestering the otherwise transcriptionally active dimer in an inactive state in the cytosol. Upon exposure of the cell to various stimuli such as increase in oxidative stress, two specific serine residues are rapidly phosphorylated by the IKK1/2 kinases, whose activity is coupled to upstream signaling cascades by their association with a third protein, called NF{kappa}B essential modulator (NEMO). Once phosphorylated, I{kappa}Bs undergo degradation via the ubiquitin–proteasome pathway in this main route of NF{kappa}B activation. This is mediated by initial recognition of phosphorylated I{kappa}Bs by the β-TrCP component of the ubiquitin ligase complex Skp1/Cul1/ROC1/F-box protein FWD 1 and subsequent covalent attachment of multiple moities of ubiquitin to the I{kappa}Bs. The multi-ubiquitin chain allows subsequent association with the amino-terminal domain of valosin-containing protein (VCP), and thereby the targeting of I{kappa}Bs to the 26S proteasome and the translocation of the transcriptionally active dimers to the nucleus. Worth noticing is the fact that the very same IKK/E3 combination is also involved in generation of p50 (NF{kappa}B1) from its precursor molecule p105 by limited proteolysis, adding to its NF{kappa}B activating function.

 
NF{kappa}B activation also leads to the expression of a number of cell survival- and proliferation-related genes, which relates to the role of the ubiquitin–proteasome system in cell survival and proliferation. This is furthermore underscored by the fact that genes, which are controlled by NF{kappa}B, encode, for instance, for inhibitor of apoptosis (IAP) proteins, including c-IAP1, c-IAP2, and XIAP, which have been identified as ubiquitin ligases, mediating functional modification and degradation of effector molecules in apoptotic cells such as caspase-3 [41–43]. Moreover, the ubiquitin–proteasome system is centrally involved in the negative regulation of the biological activity of the pro-apoptotic transcription factor p53 by virtue of ubiquitin ligase murine double minute clone 2 (MDM-2). MDM-2 facilitates transfer of p53 out of the nucleus and promotes the ubiquitination and degradation of p53 by the proteasome complex, leading to a reduction of the expression of negative cell cycle regulators such as cyclin-dependent kinase inhibitor p21WAF1/Cip1 and pro-apoptotic mediators such as Bax [44,45]. In addition, a direct, degradation-related role in the half-life regulation of p21WAF1/Cip1 and Bax has been attributed to the ubiquitin–proteasome system [46,47]. Furthermore, it mediates the degradation of the cell cycle regulators cyclin A, B, D, and E and the cyclin-dependent kinase inhibitor p27Kip1, allowing cell cycle progression and particularly entry into and completion of the S-phase of the cell cycle [48].

Given the number of both positive and negative cell cycle regulators affected, it is actually no surprise that the ubiquitin–proteasome system has been related to apoptosis as well [41,48,49]. Most profoundly, autoubiquitination of IAPs and their subsequent degradation by the proteasome is central to apoptosis as it removes their potent inhibitory impact upon caspases and hence progression of the cell death program [50]. Whether pro- or anti-apoptotic effects of the ubiquitin–proteasome system are going to prevail seems to be dependent on a number of factors, yet to be identified in their full extent. Certainly, the functional state of the ubiquitin–proteasome system itself can be an important determinant of the effect of the system upon cell survival.

Thus, the functions of the ubiquitin–proteasome system cover more than just protein disposal and include important biological processes such as inflammation, proliferation, and apoptosis, which are integral parts of the initiation, progression, and complication stage of atherosclerosis, respectively.


   4. The ubiquitin–proteasome system in the initial stage of atherosclerosis
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According to the response-to-injury theory, atherosclerosis is initiated as an inflammatory-proliferative response to an injurious stimulus, constitued by cardiovascular risk factors such as hypercholesterolemia, hypertension, smoking, diabetes, and age [51]. This injurious stimulus seems to be aggravation of endogenous oxidative stress, leading to the oxidative modification of lipids, proteins, and DNA, and thereby to structural and functional alterations within the vascular wall [52,53]. Reduction in the bioavailability of nitric oxide (NO) due to increased production of reactive oxygen species is another important pathophysiologic element in atherogenesis [54]. Under normal conditions, NO is constitutively produced by endothelial cells, antagonizing pro-atherosclerotic processes in part by suppressing the transcriptional activity of NF{kappa}B, which has been identified as a pivotal mediator in the inflammatory-proliferative process of atherogenesis [55–60]. Reduction in NO bioavailability as well as alteration of cell signaling pathways due to increase in oxidative stress, therefore, leads to the activation of NF{kappa}B [36].

Previous reports questioned the necessity of the involvement of the ubiquitin–proteasome system in NF{kappa}B activation, particularly under conditions of aggravated oxidative stress [61,62]. In human umbilical vein endothelial cells as well as in tissue derived from the right atrium from patients undergoing coronary artery bypass grafting, NF{kappa}B activation was noted even in the absence of I{kappa}B{alpha} degradation upon exposure to hydrogen peroxide and/or to a hypoxia–reoxygenation sequence [63]. Also 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, which can be found in atherosclerotic lesions, has been shown to directly activate NF{kappa}B [64]. These reports have to be viewed together with those studies that demonstrated an impairment of the ubiquitin–proteasome system under conditions of oxidative stress and by HNE [65,66]. In cultured lens epithelial cells, exposed to H2O2, a reversible impairment of ubiquitination activity was noted, which was attributed to oxidation of glutathione and subsequent glutathiolation of the active-site sulfhydryls of ubiquitin activating and conjugating enzymes [67–69]. In addition to the consideration of the 26S proteasome as being fairly sensitive to oxidative inactivation, there are a number of reports on the redox modulation of 20S proteasome proteolytic activity in vitro and in vivo, for instance by reaction with products of lipid peroxidation [70–72].

In contrast to these reports, a very recent study demonstrated the accumulation of ubiquitin conjugates in coronary arteries of pigs on a high-cholesterol diet for 12 weeks in the presence of unimpaired 20S proteasome proteolytic activity [73]. Hence, at least in this in vivo model of early atherogenesis, the ubiquitin–proteasome system remains functionally unimpaired despite increased oxidative stress [74]. Further studies will be necessary to clearly define the nature of the ubiquitin conjugates that accumulate in the coronary artery wall in (this model of) early atherogenesis. It may well be that these are hydrophobic protein aggregates, formed as the generation of oxidatively modified proteins exceeds the unimpaired proteolytic capability of the proteasome. These protein aggregates become increasingly cross-linked and thereby excellent substrates to the ubiquitination system but increasingly resistant to degradation of the proteasome.

Alternatively, these ubiquitin conjugates may reflect turnover proteins, which are increasingly generated during oxidative stress and remain digestible substrates for the ubiquitin–proteasome system such as I{kappa}B. At least in this model, concomitant antioxidant vitamin supplementation prevents NF{kappa}B activation in parallel with preservation of the accumulation of ubiquitin conjugates [73,75]. Thus, there is some initial evidence for a pathophysiologic role of the ubiquitin–proteasome system in the initial stage of atherogenesis, which may well be related to the NF{kappa}B activation pathway. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the ubiquitin–proteasome system.


   5. The ubiquitin–proteasome system in the progression stage of atherosclerosis
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The progression stage of atherosclerosis is primarily marked by the proliferation of cells attracted to the site of injury in the initial response phase.

Early evidence for a pathophysiologic role of the ubiquitin–proteasome system in the proliferative aspects of cardiovascular disease was the intense ubiquitin nuclear immunoreactivity in intimal thickening lesions, induced by the exposure of the aorta to a cannulized silicon [76]. Further support for the contribution of the ubiquitin–proteasome system to progression of atherogenesis was given by an in vitro study, demonstrating the functional significance of the ubiquitin–proteasome system for the transition of vascular smooth muscle cells (SMCs) from a contractile to a metabolic, proliferative phenotype [77]. Increase in ubiquitination in neointimal areas might, therefore, reflect breakdown of myofibrillar proteins in vascular SMCs, turning more and more into the proliferating phenotype. In accordance with this theory, co-localization of ubiquitin and {alpha}-SMC actin immunreactivity was primarily seen at the base of neointimal regions of atherosclerotic human coronary arteries (Fig. 3). A recent study demonstrated a dose-dependent inhibition of proliferation and induction of apoptosis of cultured vascular SMCs after treatment with proteasome inhibitors in association with a decrease in NF{kappa}B activation susceptibility and increase in p53 and p21 levels [78]. These findings relate well to the aforementioned role of the ubiquitin–proteasome system in cellular proliferation by antagonistic modulation of the activity of the anti- and pro-apoptotic transcription factors NF{kappa}B and p53.


Figure 3
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  		Fig. 3 Double immunostaining for ubiquitin (brown) and smooth muscle cell {alpha}-actin (red) of the coronary arterial wall from patients with fatal myocardial infarction (area adjacent to the plaque). Immunoreactivity for ubiquitin is most pronounced at the base of the neointima (arrow), and the intensity of staining for both, ubiquitin and {alpha}-actin becomes weaker towards the lumen (left hand side). Original magnification 75 x .

 
Importantly, in rodent experiments, it was noticed that just one single local administration of the proteasome inihibitor MG-132 for 5 min after endothelial denudation of carotid arteries reduces neointima formation by 75% [78]. This was associated with a decreased macrophage infiltration and SMC proliferation and increased cell apoptosis in the injury area [78]. In the only other cardiovascular in vivostudy published on this subject so far, proteasome inhibition was found to reduce vascular hypertrophy in DOCA-salt hypertensive rats [79]. This was related to a reduction in the expression of endothelin-1, hence suggesting a link between the ubiquitin–proteasome system and the endogenous endothelin system [79]. Based on recent findings, NF{kappa}B may be the molecular link between these two systems [80].

The ubiquitin–proteasome system may also be involved in foam cell formation. This theory was forwarded based on the finding that aggregated LDL (agLDL) induce the expression of the ubiquitin-conjugating enzyme E2-25K in human monocytes in association with polyubiquination of intracellular proteins and the suggestion that agLDL stimulate the ubiquitin–proteasome pathway and subsequent degradation of pro-apoptotic proteins [81]. Oxidized LDL (oxLDL) might have the same effect, although in high concentration it can inhibit the proteasome [82]. This may eventually lead to accumulation of potentially cytotoxic molecules, which, together with a prolongation of the half-life of p53 and a reduction in survival factors such as NF{kappa}B, would induce programmed cell death. Indeed, in an autopsy-based, immunohistochemical study we were able to demonstrate an increase in ubiquitin/ubiquitin conjugates in co-localization with macrophages and TUNEL-positive cells in the area of the lipid core [83]. Correlation of proteasome proteolytic activity with these findings, however, remains to be awaited. As for now, initial studies at least indicate that, depending on its activity, the ubiquitin–proteasome system relates to cell survival and/or cell death with potential significance for overall progression of atherosclerosis.


   6. The ubiquitin–proteasome system in the complication stage of atherosclerosis
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A thin fibrous cap and a large lipid core in association with inflammatory cell infiltration, apoptosis of blood-borne and vascular cells, decrease in collagen production, and increase in collagen degradation are key characteristics of the unstable atheroma [84].

T cells have been identified as a characteristic inflammatory element of atherosclerosis, contributing to plaque progression and complication [85,86]. Their pathophysiologic role is highlighted by their accumulation at the rupture-prone sites of the plaque shoulder regions and their capability to stimulate the secretion of matrix-degrading enzymes from macrophages [87–89]. Proper activation of T (helper) cells requires co-stimulation via CD28 with potential involvement of the ubiquitin–proteasome system as outlined above [89]. This may explain the high level of ubiquitin immunoreactivity displayed by T cells in complicated plaques, a finding that relates to earlier reports on the considerable fraction of T cells in the plaque area expressing the IL-2 receptor in patients with refractory unstable angina and acute myocardial infarction with pathophysiological meaning [83,90]. It has to be noted, though, that up to 40% of all T cells in unstable plaques display the CD4+/CD28– phenotype, questioning the pathophysiological significance of the ubiquitin–proteasome system via the CD28-co-stimulatory route [89,91]. Given its involvement in the metabolism of TCR units, an inhibitory rather than a stimulating effect upon T cell activity has to be considered for the ubiquitin–proteasome system [92,93]. As TCR stimulation usually precedes TCR downregulation, ubiquitin immunoreactivity of T cells in unstable plaque may nevertheless indicate T cell activation [30]. Finally, it has to be mentioned that the ubiquitin–proteasome system is also centrally involved in the activation of CD8+ T cells, also present in unstable plaques albeit in lower number than CD4+ T cells [25].

Furthermore, production of extracellular matrix proteins in atherosclerotic plaques slows down as a consequence of IFN{gamma} release from activated T cells, which can even trigger SMC apoptosis in association with TNF{alpha} and IL-1β, released from activated macrophages [94,95]. Worth noticing is the fact that these cytokines also increase the expression of the death receptor Fas (CD95) on the surface of SMCs and thereby the chances of the activation of the external pathway of apoptosis following the interaction with Fas ligand, expressed, for instance, on T cells [90]. It has been demonstrated that ubiquitin-conjugating enzyme No. 9 (Ubc 9), also known as ubiquitin-conjugating Fas-associated protein (UBC-FAP), is involved in the downstream-receptor pathway of Fas [96], and is particularly critical for Fas-mediated apoptosis [97]. Yet the action of Ubc 9 seems to relate more to an attenuating effect upon Fas signaling via the ubiquitin-like small ubiquitin modifier (SUMO) system, which frequently competes with the ubiquitin system for the lysine residue of the target protein, thereby inhibiting, for instance, protein degradation via the ubiquitin–proteasome system [98,99]. More important with regard to apoptosis in unstable plaque may be functional impairment of the ubiquitin–proteasome due to the overwhelming action of oxLDL or aggregated proteins with subsequent prolongation of the half-life and transcriptional activity of p53, i.e. the triggering of the internal pathway of apoptosis [82,100]. Indeed, p53 accumulation has been demonstrated in human atherosclerotic plaques, and atherosclerotic plaque rupture was facilitated in apolipoprotein E-deficient mice after adenovirus-mediated transfer of p53 into the SMC-rich cap region [101,102]. In this latter study, p53 overexpression resulted in a marked increase in cell apoptosis and decrease in extracellular matrix in the cap region. These experimental results underscore the association of p53, ubiquitin, and TUNEL-positive neointimal cells in the cap region of unstable plaques from patients with fatal myocardial infarction [83]. Of further notice, ubiquitin immunoreactivity was higher in cap and shoulder regions of these lesions of infarct-related arteries [83].

Thus, there may be a potential involvement of the ubiquitin–proteasome system in the pathogenesis of acute coronary syndromes with diverse cellular and intracellular targets and modes of actions. Among the most pertinent modes to mention are the contribution of the ubiquitin–proteasome system to the formation and growth of the lipid core and the potential involvement of the ubiquitin–proteasome system in the modulation of the function and viability of T cells and neointimal SMCs with outmost significance for plaque stability.


   7. Therapeutic implications
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During recent years, a number of substances have become available which readily penetrate the cell membrane and inhibit the proteolytic function of the proteasome complex [102,103]. Class-termed as proteasome inhibitors, these substances either interfere with the nucleophilic attack of a regular substrate by forming a transition state analogue or bind to the N-terminal active sites of the beta-subunits of the 20S proteasome in a pseudo-substrate manner. The primary inhibitory effect is upon the chymotrypsin-like function of the 20S proteasome, which, nevertheless, seems to be sufficient for a profound inhibition of overall proteasome proteolytic function. Similarities and differences of the current subclasses of proteasome inhibitors are provided in Table 2.


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  		Table 2 Classes and characteristics of proteasome inhibitors

 
So far, the majority of data relating to the effects of proteasome inhibitors have been obtained from cancer studies. In both in vitro and in vivo studies, it was found that proteasome inhibitors exert a substantial anti-proliferating effect, which was attributed to an increase in the activity of pro-apoptotic factors such as p53, p21, and Bax [104]. Findings of a sustained anti-proliferating effect even in p53-mutant models, however, pointed towards the significance of other factors like the survival factor NF{kappa}B and even more the negative cell cycle regulator p27 [105]. Most likely, it is a combined effect, explaining the efficiacy of this class of drugs in a broad range of tumors, including solid and hematopoetic cancers and even those resistant to chemo- or radiotherapy [106,107].

To which extent this relates to the cardiovascular system remains to be awaited from ongoing and future studies. Initial reports on the effects of proteasome inhibitors in cardiovascular diseases, however, indicate that proteasome inhibition might be an effective therapeutic strategy for the reduction of the proliferative phenomena of the progression stage of atherogenesis and restenosis after balloon angioplasty and stent implantation [77–79]. Recent data on the beneficial effect of proteasome inhibitors in hypertensive rats, correlating with a reduction of ET-1 expression, and very recent data on the improvement of endothelium-dependent vasorelaxation in vitro, correlating with an increase in eNOS expression, suggest a therapeutic potential of proteasome inhibition in the early stages of cardiovascular diseases [79,108]. Finally, it is worth noticing that for aspirin and statins, two of the most successful drugs in cardiovascular diseases, a proteasome inhibitory effect has been described [109]. If this is an effect which relates to their clinical benefit, however, awaits further investigation.

As a word of caution, it has to be mentioned that different cell populations can react differently to proteasome inhibition, and rather a pro-inflammatory and anti-apoptotic effect can be seen, for instance, in neuronal cells [110]. Also, differences in response with regard to the disease stage have to be taken into consideration; for instance, promotion of SMC apoptosis may ultimately diminish plaque stability [111]. Another more general concern is the lack of pathway specificity of proteasome inhibition. However, specific targeting of different subtypes of the proteasome, e.g. the immunoproteasome, and specific tragetting of different degrees of inhibition may allow more specific approaches in the future.


   8. Summary
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The ubiquitin–proteasome system is the main route of cellular protein degradation. In addition to its role in the removal of damaged proteins, the ubiquitin–proteasome system is involved in a number of biological processes including inflammation, proliferation, and apoptosis. From what can be gathered from the very few studies on the ubiquitin–proteasome system in cardiovascular diseases published so far, the system seems to be functionally active to a different extent in the initiation, progression, and complication stage of atherosclerosis. These early findings need further attention and confirmation, importantly with regard to therapeutic intervention, which would be indicated only if the system was clearly found to be active and pathophysiologically involved. Exogenous inhibitors of proteasome inhibitors are available and have been successfully introduced as an adjunctive treatment option in cancer. Whether this translates to the proliferative aspects of atherosclerosis and restenosis remains to be cautiously awaited.


   Acknowledgements
 
This work was supported by the National Institutes of Health (R01 HL63911-04, K24 HL69840-01), the Miami Heart Research Institute, and the Mayo Foundation. Dr. Amir Lerman is an Established Investigator of the American Heart Association.


   Notes
 
Time for primary review 29 days


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 3. The function of...
 4. The ubiquitin-proteasome...
 5. The ubiquitin-proteasome...
 6. The ubiquitin-proteasome...
 7. Therapeutic implications
 8. Summary
 References
 

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