In middle-aged patients, the seven-year incidence of myocardial infarction among patients without diabetes who had preexisting CHDwas similar to that among patients with diabetes who did not have CHD, suggesting that type 2 diabetes may confer the same degree of risk as preexisting CHD [
58]. The issue of the association between diabetes and CHD is likely to become more important, for two reasons. First, the incidence of type 2 diabetes is increasing among both high-risk populations and low-risk populations [
59]. Second, although there has been a marked decline in the rate of death due to CHD in the overall population over the past 35 years, this has not been the case among persons with diabetes [
60]. The reason for the difference is not known, but it may be that patients with diabetes have not benefited from reductions in risk factors for cardiovascular disease. This possibility is clearly not the explanation, since the reduction in the risk of CHD resulting from lipid reduction [
61] and blood-pressurereduction [
62] is similar for those with diabetes and those without. Moreover, the standard multitargeted intervention in the Steno-2 Studyshowed an event rate of the combined cardiovascular end point of 7% per year [
63]. Although the intensified intervention involving multiple risk factors cut this event rate by half, it is still more than three times as high as in the matched background population, leaving muchroom for improvements. Thus, the diabetic status, independently from the classical cardiovascular risk factors, may influence the atherosclerotic plaque progression from stable to vulnerable, and so toward a subject susceptible to an acute coronary syndrome or sudden cardiac death based on plaque rupture, namely "cardiovascular vulnerable patients" [
64]. In recent years, it has been firmly established that inflammationcontributes to plaque rupture and cardiovascular events [
65]. However, little is known about the potentially unique features of this inflammatory process in diabetes. Several inflammatory markers have been identified in atherosclerotic lesions. Among them are cytokines and growth factors, which are released by activated macrophages that, together with T cells, are major cellular components in atherosclerotic lesions [
66]. Cytokines increase the synthesis of platelet activating factor, stimulate lipolysis, markedly stimulate the expression of adhesion molecules, and upregulate the synthesis and cell surface expression of procoagulant activity in endothelial cells. Thus, cytokines may play a crucial role in the progression of atherosclerotic lesions toward instability. However, even if the inflammatory burden linked to diabetes not only may lead to the initiation and progression of atherosclerosis but also may contribute to plaque rupture and cardiovascular events, not much is known about inflammatory plaque differences as well as the plaque phenotype in subjects with versus those without diabetes. A thin fibrous cap and a large lipid core in association with inflammatory cell infiltration and necrotic areas, apoptosis of blood-borne and vascular cells, decrease in collagen production, and increase in collagen degradation are key characteristics of the unstable atheroma [
67]. In atherectomy specimens, the cell-rich and necrotic areas are increased in de novo lesions in persons with diabetes [
68]. In a series of coronary arteries examined after sudden death, the extent of the necrotic core of plaques, calcification, and healed ruptures were increased in patients with type 2 diabetes [
69]. Moreover, atherosclerotic lesions from diabetic patients were characterized by higher apoptosis of VSMC, higher NFkB activation and MMP-9 levels along with a lesser interstitialcollagen content [
70]. So, all this might increase the risk of future acute ischemic events precipitated by inflammatory-dependent rupture of atherosclerotic plaques. The mechanisms linking inflammation with plaque rupture in diabetes are not clear. It is well recognizedthat inflammation is one manifestation of oxidative stress [
71] and the pathways that generate the mediators of inflammation, such as adhesion molecules and interleukins, are all induced by oxidative stress [
72]. There are several studies demonstrating that patients with diabetes not only have increased levels of circulating markers of free radical-induced damage, but also have reduced antioxidant defenses [
73]. Although these processes can be potentiated by diabetes and can contribute to the plaque rupture the molecular mechanisms linking inflammation and oxidative stress with CHD in diabetic plaques are not fully clarified. However, there is emerging evidence about the potential role of UPS also in the evolution of diabetic atherosclerotic plaques toward instability, as evidenced by the observation that the ubiquitin-proteasome pathway is required for activation of NFkB by degradation of its inhibitory IkB proteins [
74]. Thus, oxidative stress the common factor underlying insulin-resistance, type 2 diabetes mellitus and CHD, may explain the presence of inflammation in all these conditions [
75]. In this context, recent data suggest an interesting mechanism by which oxidative stress, increasing ubiquitin-proteasome activity, may mediate inflammatory activity in diabetic atherosclerotic plaques. Macrophages, T-lymphocytes and HDLA-DR+ inflammatory cells were more abundant in diabetic than in nondiabetic plaques and represented the major source of ubiquitin-proteasome activity, suggesting the presence of an active inflammatory reaction in diabetic lesions [
48]. Moreover, in agreement with the difference in ubiquitin-proteasome staining pattern, thehistological milieu of the lesions appears different with regard to cellularity, but not in the degree of vessel stenosis, suggesting that diabetic and nondiabetic lesions are only different as regard to inflammatory burden. 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]. Accordingly, in cultured monocytes from diabetic patients it has been evidenced that O2
- production as well as ubiquitin-proteasome activity and NFkB levels were significantly higher when compared to nondiabetic patients [
48]. Thus, it has been proposed that 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 diabetic plaque instability (Figure
2). In line with this construct, the observations that the ubiquitin-proteasome activity was greater in diabetic atherosclerotic lesions as compared to nondiabetic lesions, and was associated with higher NFkB and MMP-9 levels along with a lesser interstitial collagen content, suggest that this system may have an important role in the inflammatory process ofatherosclerotic plaques of type 2 diabetic patients. However, the UPS upregulation may increases the MMP-9 expression through NFkB activation, which is known to regulate MMPs activity [
76].