Atherosclerosis

The Big Heart Disease Lie

Treating  Cardiovascular Disease

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For long time, hypercholesterolaemia has been claimed as be the most important risk factor for atherogenesis. However, recently it has been appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation and inflammatory processes play an important role for the progression of atherosclerosis.26 Thus, atherosclerotic patients display a pro-inflammatory phenotype and the control of inflammation might play a protective role in atherosclerosis complications, including acute myocardial infarction. Indeed, atherosclerosis is now better described as an inflammatory disease of the vessel wall, characterized by the accumulation of lipid-laden macrophages and fibrous material in the large arteries and flared plaque inflammation is considered a cause of intimal erosion and rupture and therefore of acute ischaemia.26-28 Studies in vitro and in experimental animals are supported by the clinical finding of increased inflammatory markers in patients with chronic stable angina, severe unstable angina, and acute myocardial infarction and by the predictive value of such a marker as C reactive protein (CRP) for subsequent coronary events.29,30 An initiating event is the accumulation of lipids in the vessel wall, which subsequently will become modified and trigger an inflammatory process. Low-density lipoproteins (LDL) are taken up by macrophages through scavenger receptors, leading to foam cells; the lipid deposits become oxidized forming pro-inflammatory lipid peroxides. Monocytes are attracted from the blood and differentiate into macrophages that take up the modified LDL and will form lipid-laden foam cells, which is the first hallmark of atherosclerotic plaque development. Later on, inflammatory mediators will increase, other immune cells will be attracted, and smooth muscle cells will be activated and become involved. More advanced stages of plaque development are characterized by increased deposition of extra cellular lipid cores, fibrous material, and often necrosis. Subsequently, these macrophages are further activated, leading to the production of a wide range of cytokines and growth factors. Myocardial infarction may occur as a result of erosion or uneven thinning and rupture of the fibrous cap, often at the shoulders of the lesion where macrophages enter, accumulate and are activated and where apoptosis may occur.26-28,31

Several lines of evidence indicate an involvement of IL-10 in the development of atherosclerosis. In fact, IL-10 can limit the progression of experimental atherosclerosis.7 IL-10—deficient knockout mice have a thirty-fold increase in susceptibility to atherosclerosis, due either to high cholesterol diet,32 or to a cardiac allograft vasculopathy setting.33 The transfection of adenovirus-mediated over expression of IL-10 into the LDL-receptor knockout mouse strongly inhibits the otherwise rapidly growing atherosclerotic lesions. IL-10 has several anti-atherogenic effects including inhibition of adhesion of LDL—activated monocytes to endothelium and down regulation of fibrinogen biosynthesis.34-36

IL-10 is detectable in human atherosclerotic plaques26 and has been claimed to plays a regulation role in progression of atherosclerosis human coronary artery disease. A study compared 50 patients with stable and 45 patients with unstable angina pectoris. Plasma IL-6 levels where significantly higher and plasma IL-10 levels lower in those patients with the unstable form of the disease.37

Besides, serum level of IL-10 may be an important prognostic determinant in patients with acute coronary syndromes.38 In this study, IL-10, CRP, and troponin T were measured at baseline and before discharge in 547 patients. Patients with elevated IL-10 levels were at significantly lower risk compared with patients with low IL-10 levels. The predictive value of IL-10 showed also a significant interaction with well known risk factor CRP levels. CRP-positive patients with the higher IL-10 serum levels were protected from the increased cardiac risk of CRP-positive patients with low IL-10 levels.38

Recently it has been reported that protective effect of IL-10 in atherosclerosis may be linked to the effect of NF-kB regulation pathway.39 The transcription factor NF-kB is one of the key regulators of inflammation, immune responses, and cell survival. Upon activation, NF-kB can mediate the induction of more than 160 genes, many of which have a documented role in atherogenesis.40 Activated NF-kB has been detected in endothelial cells, smooth muscle cells, and macrophages in atherosclerotic plaques.41 In resting cells, NF-kB dimers are kept inactive associated with inhibitory proteins, the IkBs. NF-kB activation is mediated by the IkB kinase (IKK) complex containing two catalytic subunits, IKK1 (IKKa) and IKK2 (IKKP), and a regulatory subunit called NF-kB essential modulator (NEMO or IKKy). Upon stimulation, the IKK complex phosphorylates IkB, inducing its ubiquination and subsequent degradation. NF-kB is then free to the translocation to the nucleus where it facilitates the transcription of many genes, including cytokines, chemokines, and anti-apoptotic factors.42

A lot of circumstantial evidence has indicated a potential role for NF-kB in atherosclerosis. First of all, activated NF-kB has been demonstrated in human atherosclerotic plaques, in macrophages, smooth muscle cells, and endothelial cells.40 Moreover, several NF-kB regulated genes have been demonstrated to be unregulated in plaques, including pro-inflammatory cytokines, such as tumor necrosis factor(TNF)-a and IL-6.43 Additionally, receptors that can signal to NF-kB are also present in lesions, including several member of the toll-like receptor family, which also mediate signal-induced activation of macrophages.44 In an animal experimental model the inhibition or deletion of IKK2 regulatory protein in macrophages enhances atherosclerosis.39 One of the effects of IKK2 deletion in macrophages results in a reduction in IL-10 and may be regarded as pro-atherogenic phenomenon.39 However, through which mechanisms and genes NF-kB is involved in the development of atherogenesis and its role in pro-inflammatory/anti-inflammatory balance remain challenging questions for future research.39

IL-10 seems also able to attenuate CD40-mediated interleukin-12 synthesis in human endothelial cells through induction of nitric-oxide synthase expression.45 It has been reported, in fact, that under pro-inflammatory conditions expression of the human IL-10 receptor gene is enhanced in endothelial cells in vitro and in vivo and exposure to IL-10 results in an up-regulation of both endothelial nitric-oxide synthase (e-NOS) expression and activity through activation of the transcription factor STAT-3. CD154-induced IL-12 p40 expression is enhanced after blockade of e-NOS activity but attenuated in the presence of exogenous nitric oxide. Increased e-NOS-3 expression may, thus, be one mechanism by which IL-10 exerts its anti-inflammatory effects in type 1 cell-mediated chronic inflammatory diseases.45

Moreover the latter effect might attribute a role for IL-10 secretion in the control of blood pressure. It has been hypothesized that a rise in blood pressure (BP) activates a vicious cycle, causing chronic inflammation of the endothelium, which in turn might be responsible for a further damage of endothelium and worsening of BP control with activation of pro-and anti-inflammatory molecule production.46 A sustained IL-10 production by endothelial cells might induce in the same cells nitric oxide production by autocrine effect with potentially positive effects on BP control.

Accumulating evidence suggests that inflammation plays an important role not only in the development of cardiovascular but also in cerebrovascular disease.47-49 Markers of inflammation, such as CRP29,3048,49 and pro-inflammatory cytokines are associated with stroke.50 Analysis of the association between low IL-10 production levels and natural history of stroke episodes.48 shows that low IL-10 production levels are associated with both a history of stroke, in a cross-sectional study, and increased mortality due to stroke, as obtained in a prospective follow-up study. These associations persisted after adjustment for known risk factors for stroke. An inverse relationship was found between CRP, one of the most sensitive detectable signals of inflammation, and IL-10 levels in association with stroke.47,48,51 CRP and IL-10 at least partly represent the effect of an inflammatory response on stroke. Studies of cerebral ischemia emphasize the relevance of an inflammatory response in regard to lesion size, in which IL-10 is a key re gulator.7,52,53 IL-10 , as a powerful suppressor of proinflammatory cytokines such as TNF-a and IL-6,7 may also inhibit CRP, since it has been suggested that IL-6 is implied in regulation of CRP production.54

Similar results were obtained evaluating the IL-10 levels in patients with neurological worsening after acute ischemic stroke. Lower plasma concentrations of IL-10 were associated with clinical worsening and in particular early worsening was, independently by other risk and clinical factors, associated with lower IL-10 plasma levels in patients with subcortical infarcts or lacunar stroke.55

These reports seem to attribute a protective role to anti-inflammatory effects of IL-10 in stroke, and, considering its effect on the reduction of brain ischemic damage size in experimental model of cerebral arteries occlusion,53 may indicate a potential therapeutic role for this cytokine. In Figure 1 we show our suggestion on the multiple inhibitory effects of IL-10 on pathogenetic mechanisms of atherosclerosis.

Concerning the role of the genetic control of IL-10 production in atherosclerosis development, case-control studies across Europe do not support any role for IL-10 in either atherosclerotic-related disease or myocardial infarction.5 However, a more recent study suggests that -1082AA genotype, which is associated with low production of the cytokine IL-10 and elevated markers of systemic inflammation such as C reactive protein, was predictive for a

Figure 1. The figure depicts the multiple inhibitory effects of IL-10 on pathogenetic mechanisms of atherosclerosis. The role of NFkB, cytokines, chemokines (MCP-1), adhesion molecules (VCAM-1) is outlined.

higher cardiovascular morbidity in dialysis patients compared to the -1082GG genotype. In fact, in a group of haemodyalised patients sequential measures of plasmatic C-reactive protein levels allowed to find that patients with the IL-10 "high-producer" genotype had significantly less variation and less elevation of CRP levels.58 Inflammatory mediators are induced in all patients with chronic renal failure due to uraemia and renal replacement therapy. However, while those with the IL-10 "high-producer" genotype may effectively limit inflammation, this is not the case in the "low-producer" group. So, it was observed a significantly higher risk both for events and cardiovascular mortality in patients with the IL-10 "low-producer" genotype. These data impressively confirm the important role of IL-10 for the protection of the individual against the long-term effects of systemic inflammation.58 A recent report in two Italian samples of patients affected by myocardial infarction seems also to suggest a role for IL-10 polymorphism linked to low cytokine production in the occurrence of the disease.59 These last data are in agreement with the role in Italian population of IL-10 low-producer genotype in attainment of longevity.21,23

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