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The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes.

Marfella R, D' Amico M, Di Filippo C, Siniscalchi M, Sasso FC, Ferraraccio F, Rossi F, Paolisso G - Cardiovasc Diabetol (2007)

Bottom Line: People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes 1.Furthermore, diabetic patients have not benefited by the advances in the management of obesity, dyslipidemia, and hypertension that have resulted in a decrease in mortality for coronary heart disease (CHD) patients without diabetes 3.Nevertheless, these risk factors do not fully explain the excess risk for CHD associated with diabetes 45.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. raffaele.marfella@unina2.it

ABSTRACT
We have reviewed the impact of the ubiquitin proteasome system (UPS) on atherosclerosis progression of diabetic patients. A puzzle of many pieces of evidence suggests that UPS, in addition to its role in the removal of damaged proteins, is involved in a number of biological processes including inflammation, proliferation and apoptosis, all of which constitute important characteristics of atherosclerosis. From what can be gathered from the very few studies on the UPS in diabetic 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 in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and cardiovascular diseases (CVD). People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes 1. The prevalence, incidence, and mortality from all forms of CVD (myocardial infarction, cerebro-vascular disease and congestive heart failure) are strikingly increased in persons with diabetes compared with those withoutdiabetes 2. Furthermore, diabetic patients have not benefited by the advances in the management of obesity, dyslipidemia, and hypertension that have resulted in a decrease in mortality for coronary heart disease (CHD) patients without diabetes 3. Nevertheless, these risk factors do not fully explain the excess risk for CHD associated with diabetes 45. Thus, the determinants of progression of atherosclerosis in persons with diabetes must be elucidated. Beyond the major risk factors, several studies have demonstrated that such factors, strictly related to diabetes, as insulin-resistance, post-prandial hyperglycemia and chronic hyperglycemia play a role in the atherosclerotic process and may require intervention 67. Moreover, it is important to recognize that these risk factors frequently "cluster" inindividual patients and possibly interact with each other, favouring the atherosclerosis progression toward plaque instability. Thus, a fundamental question is, "which is the common soil hypothesis that may unifying the burden of all these factors on atherosclerosis of diabetic patients? Because evidences suggest that insulin-resistance, diabetes and CHD share in common a deregulation of ubiquitin-proteasome system (UPS), the major pathway for nonlysosomal intracellular protein degradation in eucaryotic cells 89, in this review ubiquitin-proteasome deregulation is proposed as the common persistent pathogenic factor mediating the initial stage of the atherosclerosis as well as the progression to complicated plaque in diabetic patients.

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In this model, atherosclerosis process results from pathophysiological activity of UPS that may activate the NFkB inflammatory activity in the plaque macrophages. Activation pathway of NFkB, a homo- or heterodimeric transcription factor, composed by members of the Rel family of proteins. The classical example of NFkB 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 IkB family, primarily IkBα and IkBβ. 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. Once phosphorylated, IkBs undergo degradation via the ubiquitin-proteasome pathway in this main route of NFkB activation.
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Figure 2: In this model, atherosclerosis process results from pathophysiological activity of UPS that may activate the NFkB inflammatory activity in the plaque macrophages. Activation pathway of NFkB, a homo- or heterodimeric transcription factor, composed by members of the Rel family of proteins. The classical example of NFkB 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 IkB family, primarily IkBα and IkBβ. 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. Once phosphorylated, IkBs undergo degradation via the ubiquitin-proteasome pathway in this main route of NFkB activation.

Mentions: Ciechanover [10] presented in 1978 the first description of a heat-stable polypeptide that associated with an ATP-dependent proteolytic system in reticulocytes that had been previously described by Etlinger [11] in 1977. This proteolytic complex has been known by several names, including macroxyproteinase, multicatalytic proteinase complex, prosome, and, most commonly, the proteasome [12]. The UPS is responsible for the non-lysosomal degradation of the majority of intracellular proteins [13] thus playing a crucial role in the regulation of many cellular processes. The process of ubiquitination requires various enzymatic activity, involving specific proteins (i.e. E1, E2, E3) which activate and transfer polyubiquitin chains to target proteins, leading eventually to the formation of a complex which is recognized and degraded by the 26S proteasome complex [13]. This complex is composed of a 20S core particle which embodies the catalytic activity and two 19S regulatory particles. The targets of the UPS include key regulators of cell cycle and apoptosis and various transcription factors, whose intracellular levels are finely tuned in the maintenance of the optimum equilibrium for cell division, growth, differentiation, signal transduction and response to stress [14]. In addition, the UPS plays key roles in protein quality by removal of damaged, oxidized, and/or misfolded proteins [14] (Figure 1). Many of these processes are crucially involved in the onset, progression, and complication of atherosclerosis. In particular the UPS may be influenced by oxidative stress and plays a key role in the activation of nuclear factor kappa B (NFkB) [15], which has been associated with coronary [16] and carotid [17] plaque instability. Previous studies, however, indicated that the UPS could be functionally impaired under conditions of increased endogenous oxidative stress, such as diabetes and coronary artery disease [18]. Of note, it has been shown that oxidative stress can stimulate the UPS in macrophages by inducing the expression of components of its enzymatic machinery such as ubiquitin-binding proteins [19,20]. Accordingly, in cultured monocytes from patients with cerebrovascular disease has been evidenced that superoxide anion production as well as ubiquitin-proteasome activity and NFkB levels were significantly higher when compared to patients without cerebrovascular disease [21]. NFkB is normally bound to IkB in the cytosol; this binding prevents its movement into the nucleus [21]. Oxidative stress may induce ubiquitination of phosphorylated IkBs and subsequent degradation by the proteasome [22]. Degradation of IkBs results in unmasking of the nuclear localization signal of NFkB dimers, which subsequently translocates to the nucleus, where it induces the transcription of proinflammatory cytokines that play a central role in plaque instability progression [23]. Thus, increased ubiquitin-proteasome activity in plaque macrophage as consequence of oxidative stress overexpression may enhance the synthesis of NFkB in the same cell, possibly representing a crucial step in the pathophysiology of atherosclerosis progression. Foremost, a vicious circle can also develop: increased ubiquitin-proteasome activity in atherosclerotic vessels leads to increased inflammatory activity, which in turn leads to further increments of oxidative stress and consequently may increase the ubiquitinated proteins. Thus, these biological pathways including inflammation, cell proliferation, and oxidative stress, support a potential involvement of the UPS in the initiation, progression, and complication stage of atherogenesis [9] (Figure 2).


The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes.

Marfella R, D' Amico M, Di Filippo C, Siniscalchi M, Sasso FC, Ferraraccio F, Rossi F, Paolisso G - Cardiovasc Diabetol (2007)

In this model, atherosclerosis process results from pathophysiological activity of UPS that may activate the NFkB inflammatory activity in the plaque macrophages. Activation pathway of NFkB, a homo- or heterodimeric transcription factor, composed by members of the Rel family of proteins. The classical example of NFkB 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 IkB family, primarily IkBα and IkBβ. 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. Once phosphorylated, IkBs undergo degradation via the ubiquitin-proteasome pathway in this main route of NFkB activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2169213&req=5

Figure 2: In this model, atherosclerosis process results from pathophysiological activity of UPS that may activate the NFkB inflammatory activity in the plaque macrophages. Activation pathway of NFkB, a homo- or heterodimeric transcription factor, composed by members of the Rel family of proteins. The classical example of NFkB 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 IkB family, primarily IkBα and IkBβ. 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. Once phosphorylated, IkBs undergo degradation via the ubiquitin-proteasome pathway in this main route of NFkB activation.
Mentions: Ciechanover [10] presented in 1978 the first description of a heat-stable polypeptide that associated with an ATP-dependent proteolytic system in reticulocytes that had been previously described by Etlinger [11] in 1977. This proteolytic complex has been known by several names, including macroxyproteinase, multicatalytic proteinase complex, prosome, and, most commonly, the proteasome [12]. The UPS is responsible for the non-lysosomal degradation of the majority of intracellular proteins [13] thus playing a crucial role in the regulation of many cellular processes. The process of ubiquitination requires various enzymatic activity, involving specific proteins (i.e. E1, E2, E3) which activate and transfer polyubiquitin chains to target proteins, leading eventually to the formation of a complex which is recognized and degraded by the 26S proteasome complex [13]. This complex is composed of a 20S core particle which embodies the catalytic activity and two 19S regulatory particles. The targets of the UPS include key regulators of cell cycle and apoptosis and various transcription factors, whose intracellular levels are finely tuned in the maintenance of the optimum equilibrium for cell division, growth, differentiation, signal transduction and response to stress [14]. In addition, the UPS plays key roles in protein quality by removal of damaged, oxidized, and/or misfolded proteins [14] (Figure 1). Many of these processes are crucially involved in the onset, progression, and complication of atherosclerosis. In particular the UPS may be influenced by oxidative stress and plays a key role in the activation of nuclear factor kappa B (NFkB) [15], which has been associated with coronary [16] and carotid [17] plaque instability. Previous studies, however, indicated that the UPS could be functionally impaired under conditions of increased endogenous oxidative stress, such as diabetes and coronary artery disease [18]. Of note, it has been shown that oxidative stress can stimulate the UPS in macrophages by inducing the expression of components of its enzymatic machinery such as ubiquitin-binding proteins [19,20]. Accordingly, in cultured monocytes from patients with cerebrovascular disease has been evidenced that superoxide anion production as well as ubiquitin-proteasome activity and NFkB levels were significantly higher when compared to patients without cerebrovascular disease [21]. NFkB is normally bound to IkB in the cytosol; this binding prevents its movement into the nucleus [21]. Oxidative stress may induce ubiquitination of phosphorylated IkBs and subsequent degradation by the proteasome [22]. Degradation of IkBs results in unmasking of the nuclear localization signal of NFkB dimers, which subsequently translocates to the nucleus, where it induces the transcription of proinflammatory cytokines that play a central role in plaque instability progression [23]. Thus, increased ubiquitin-proteasome activity in plaque macrophage as consequence of oxidative stress overexpression may enhance the synthesis of NFkB in the same cell, possibly representing a crucial step in the pathophysiology of atherosclerosis progression. Foremost, a vicious circle can also develop: increased ubiquitin-proteasome activity in atherosclerotic vessels leads to increased inflammatory activity, which in turn leads to further increments of oxidative stress and consequently may increase the ubiquitinated proteins. Thus, these biological pathways including inflammation, cell proliferation, and oxidative stress, support a potential involvement of the UPS in the initiation, progression, and complication stage of atherogenesis [9] (Figure 2).

Bottom Line: People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes 1.Furthermore, diabetic patients have not benefited by the advances in the management of obesity, dyslipidemia, and hypertension that have resulted in a decrease in mortality for coronary heart disease (CHD) patients without diabetes 3.Nevertheless, these risk factors do not fully explain the excess risk for CHD associated with diabetes 45.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy. raffaele.marfella@unina2.it

ABSTRACT
We have reviewed the impact of the ubiquitin proteasome system (UPS) on atherosclerosis progression of diabetic patients. A puzzle of many pieces of evidence suggests that UPS, in addition to its role in the removal of damaged proteins, is involved in a number of biological processes including inflammation, proliferation and apoptosis, all of which constitute important characteristics of atherosclerosis. From what can be gathered from the very few studies on the UPS in diabetic 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 in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and cardiovascular diseases (CVD). People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes 1. The prevalence, incidence, and mortality from all forms of CVD (myocardial infarction, cerebro-vascular disease and congestive heart failure) are strikingly increased in persons with diabetes compared with those withoutdiabetes 2. Furthermore, diabetic patients have not benefited by the advances in the management of obesity, dyslipidemia, and hypertension that have resulted in a decrease in mortality for coronary heart disease (CHD) patients without diabetes 3. Nevertheless, these risk factors do not fully explain the excess risk for CHD associated with diabetes 45. Thus, the determinants of progression of atherosclerosis in persons with diabetes must be elucidated. Beyond the major risk factors, several studies have demonstrated that such factors, strictly related to diabetes, as insulin-resistance, post-prandial hyperglycemia and chronic hyperglycemia play a role in the atherosclerotic process and may require intervention 67. Moreover, it is important to recognize that these risk factors frequently "cluster" inindividual patients and possibly interact with each other, favouring the atherosclerosis progression toward plaque instability. Thus, a fundamental question is, "which is the common soil hypothesis that may unifying the burden of all these factors on atherosclerosis of diabetic patients? Because evidences suggest that insulin-resistance, diabetes and CHD share in common a deregulation of ubiquitin-proteasome system (UPS), the major pathway for nonlysosomal intracellular protein degradation in eucaryotic cells 89, in this review ubiquitin-proteasome deregulation is proposed as the common persistent pathogenic factor mediating the initial stage of the atherosclerosis as well as the progression to complicated plaque in diabetic patients.

Show MeSH
Related in: MedlinePlus