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In other studies the concomitant association of hypertriglyceridemia and low HDL appears to obscure any additional risk profiling attributable to LDL size In dietary studies using primates, larger, not smaller, LDL size correlates with atherosclerosis, presumably because each of these LDL carries more cholesterol This can be done by measuring LDL density using an ultracentrifuge or by measuring size using gradient gels or light scattering.

Another method of determining the likelihood of a patient having small dense LDL is by waist measurement, a cheaper and easier test 38 , Obesity and insulin resistance are highly correlated with small dense LDL. Reduced HDL. There are several reasons for the decrease in HDL found in patients with diabetes Fig. Clinical measurements of HDL are of HDL cholesterol; therefore, substitution of triglyceride for cholesteryl ester in the core of the particle leads to a decrease in this measurement.

Moreover, the triglyceride, but not cholesteryl ester, in HDL is a substrate for plasma lipases, especially hepatic lipase that converts HDL to a smaller particle that is more rapidly cleared from the plasma This increases HDL lipid content. Defective lipolysis leads to reduced HDL production. Effects of diabetes on HDL metabolism. HDL production requires the addition of lipid to small nascent particles. A second pathway is via efflux of cellular free cholesterol FC , a process that involves the newly described ABC1 transporter and esterification of this cholesterol by the enzyme lecithin cholesterol acyl transferase LCAT.

HDL catabolism may occur through several steps. Hepatic lipase and scavenger receptor-BI are found in the liver and in steroid-producing cells. In contrast, the kidney degrades HDL protein apoAI without lipid, perhaps by filtering nonlipid-containing protein. Within the last 2 yr a number of additional enzymes and receptors have been discovered that are integral regulators of HDL metabolism and presumably the effects of HDL on atherosclerosis.

It is not yet clear whether hyperglycemia or insulin is an important regulator of these molecules. One of the first steps in HDL production is the addition of lipid to the small, newly formed HDL particles manufactured in the liver and intestine. Phospholipid transfer protein may be required for lipid transfer from triglyceride-rich lipoproteins In addition, newly formed HDL receive cholesterol from nonhepatic tissues. Theoretically, the most important of these tissues for atherosclerosis development should be the arterial wall and lipid-rich vessel macrophages.

Several groups have recently identified the gene responsible for Tangier disease, a rare defect associated with very low levels of HDL and deposits of cholesterol in the tonsils and other lymphoid tissues. This protein appears to be necessary for transfer of excess cholesterol out of cells and into HDL.

Cholesterol is an amphipathic molecule that would be expected to remain on the surface of a lipoprotein. Lecithin acyl transferase converts cholesterol into its hydrophobic ester form, allowing it to enter the core of the lipoprotein particle. Unlike LDL, but more akin to triglyceride-rich lipoproteins, HDL protein and lipid metabolism are sometimes disparate. Cholesterol is the substrate for steroid hormones and bile. Liver, adrenal, and gonads can obtain HDL lipid without uptake and degradation of the entire lipoprotein. This process involves scavenger receptor-BI. By controlling the return of cholesterol to the liver, this receptor appears to play an antiatherogenic role in models of mouse atherosclerosis 44 , This appears to occur due to filtration of this kDa protein when it is freed from HDL lipid.

Fatty acids may be important for this effect; these fatty acids may be derived from hepatic lipase hydrolysis of HDL triglyceride Relationship of diabetic dyslipidemia to atherosclerotic risk. Trials of glucose reduction have confirmed that glucose control is the key to preventing microvascular diabetic complications. These trials have, however, failed to show a marked benefit of glucose control on macrovascular disease.

There are several reasons why this could have occurred. The time course of the effects of diabetes on diseases of large arteries and small vessels differs 47 , and longer trials may be needed. Reversal of underlying vascular disease may require a different degree of control or may follow a different time course than that for small vessels. Finally, the pathological processes are probably different. Small vessel disease of diabetic patients occurs in both type 1 and type 2 diabetes and does not occur in nondiabetics.

It is clearly related to the defective glucose control. Large vessel atherosclerosis is not a diabetes-specific disorder, yet it is worse in patients with diabetes; however, processes unrelated to diabetes must be the most important. For this reason it may not be surprising that treatment of these other processes, such as hypertension 48 , 49 and hyperlipidemia 50 , appears to impact macrovascular disease more than does glucose control. Similarly, the incidence of coronary heart disease in a diabetic population with low plasma cholesterol levels is much less than that found in western, atherosclerosis-prone populations In contrast, the metabolic abnormalities associated with the insulin-resistant syndrome and increased coronary artery disease are found in the U.

Is it these abnormalities and not the glucose per se that are atherogenic? A variety of animal models have been used to try to reproduce the relationship between diabetes and macrovascular disease. In a classic experiment, Duff et al. In a seemingly paradoxical result the diabetic rabbits had less, not more, atherosclerosis. This atherosclerosis was increased with insulin treatment. The reasons for this result are now apparent.

These rabbits developed hyperlipidemia that was due in part to a marked defect in LpL.


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Large chylomicrons were not converted to more atherogenic remnant lipoproteins and were unable to penetrate the vessel and lead to lipid deposition This pathophysiological situation is not reproduced in human diabetes, except for the rare situation in which patients are also LpL deficient. Other animal studies have more closely imitated the situation in man.

Limited studies have been performed in monkeys made diabetic using streptozotocin; in some studies the monkeys have increased LDL retention and reduced HDL 54 , Alloxan-treated pigs develop diabetes and increased atherosclerosis 56 ; however, plasma LDL was more than doubled by the diabetes.

Thus, the effects of diabetes cannot be discerned, because increased lipoprotein levels alone should increase atherosclerosis. Within the past decade, genetic manipulation has made mice the most widely used animal for the study of human disease. For this reason, several investigative groups have studied the effects of hyperglycemia on atherosclerosis progression.

There are three well defined mouse models of atherosclerosis, and all have been studied under diabetic conditions. Park et al. In these mice the diabetes markedly increased circulating cholesterol levels, perhaps due to a decrease in liver uptake of remnant lipoproteins via the proteoglycan-mediated pathway Therefore, the secondary hyperlipidemia, rather than effects of the diabetes itself, might have been the primary reason for the increased atherosclerosis. Diabetic LDL receptor knockout mice do not have more atherosclerosis than control mice Mice that contain a transgene for expression of human apoB are more hyperlipidemic than wild-type animals and develop atherosclerotic lesions when fed a diet similar to that eaten by inhabitants of northern Europe and North America.

Addition of diabetes using streptozotocin 60 and by crossing with brown adipose tissue-deficient mice did not increase atherosclerosis in these mice If one were convinced that hyperglycemia alone is responsible for accelerated atherosclerosis, it would appear that the mouse, despite its production of AGEs, is resistant to diabetic macrovascular disease. An alternative hypothesis that is compatible with the known human data and is consistent with the mouse and other animal models is that diabetes-mediated acceleration of vascular disease requires some additional factors missing in the mouse model.

One such factor is diabetic dyslipidemia. Treatment of dyslipidemia in patients with diabetes. There are two reasons to specifically correct lipoprotein abnormalities in patients with diabetes. These are to prevent pancreatitis due to severe hypertriglyceridemia and to reduce the risk of macrovascular complications. A number of recent reviews have focused on the use of lipid-lowering medications in diabetic patients The objectives of that therapy will be discussed here. The American Diabetes Association has published clinical goals for lipoprotein levels in adults with diabetes The rationale for the LDL recommendation is based on the observations that adult patients with diabetes and no overt macrovascular disease appear to have the same risk of development of cardiac events as nondiabetics who already have had a cardiac event Most importantly, there are available medications that should allow practitioners to reach this goal in most patients.

Moreover, data exist showing that statin drugs are efficacious for LDL-lowering and disease prevention in diabetic patients. The second goal is to increase HDL to 45 or greater. Although this may be an ideal goal, for many patients and their physicians it is not a practical one. This is acknowledged in the American Diabetes Association report Exercise, weight loss, and smoking cessation all increase HDL. Diets low in cholesterol and saturated fat tend to decrease HDL. The most effective single medication to raise HDL is niacin Although niacin can be given to diabetic patients, it is generally avoided because it causes worsening hyperglycemia.

Fibric acids and statins also increase HDL; however, their effects are more modest that those found with niacin. Two recent intervention trials showed effective methods to reduce cardiac disease in subjects with low HDL.

Neither method raised HDL to the ADA goal, nor did the studies use medications that are likely to achieve this goal in most patients. In one study subjects with HDL below 50 were treated with statins; lower LDL was associated with fewer cardiac events The primary and in many cases essential approach to triglyceride reduction is glycemic control. In type 2 patients this also means weight reduction. Although severe hypertriglyceridemia leads to increased risk for pancreatitis, proof that reduction of triglycerides is of benefit is lacking.

Several investigators quote the VA-HIT trial and several subgroup analyses of fibric acid studies as evidence that treatment of elevated triglycerides is beneficial. Triglycerides can be reduced with niacin, fibric acids, high dose statins, and fish oil. It should be noted that the use of fibric acids to reduce triglyceride along with statins increases the risk of myositis and should be used with caution. Much of the pathophysiology linking diabetes and dyslipidemia has been elucidated. Although undoubtedly of importance, diabetic dyslipidemia is likely to be but one of many reasons for the accelerated macrovascular disease in diabetic patients.

This leads to the expectation that treatment of elevated lipid levels will allow patients with diabetes to lead longer healthier lives. Oxford University Press is a department of the University of Oxford. Angiotensin II AII , in addition to its vasoconstrictor properties, can instigate intimal inflammation. For example, AII elicits the production of superoxide anion, a reactive oxygen species, from arterial endothelial cells and SMCs.

Diabetes is yet another risk factor for atherosclerosis of growing importance. The hyperglycemia associated with diabetes can lead to modification of macromolecules, for example, by forming advance glycation end products AGE. Beyond the hyperglycemia, the diabetic state promotes oxidative stress mediated by reactive oxygen species and carbonyl groups.

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Obesity not only predisposes to insulin resistance and diabetes, but also contributes to atherogenic dyslipidemia. High levels of free fatty acids originating from visceral fat reach the liver through the portal circulation and stimulate synthesis of the triglyceride-rich lipoprotein VLDL by hepatocytes.

Infectious agents might also conceivably furnish inflammatory stimuli that accentuate atherogenesis. Chronic extravascular infections eg, gingivitis, prostatitis, bronchitis, etc can augment extravascular production of inflammatory cytokines that may accelerate the evolution of remote atherosclerotic lesions.

Intravascular infection might also provide a local inflammatory stimulus that could accelerate atherogenesis. Many human plaques show signs of infection by microbial agents such Chlamydia pneumoniae. Chlamydiae , when present in the arterial plaque, may release lipopolysaccharide endotoxin and heat shock proteins that can stimulate the production of proinflammatory mediators by vascular endothelial cells and SMCs and infiltrating leukocytes alike. The mechanisms of ACS encompass elements of thrombosis and vasoconstriction superimposed on atherosclerotic lesions.

Thrombosis frequently persists, detectable by angiography, by angioscopy, or at autopsy. In contrast, vasospasm presents challenges to quantification because of its transient nature. Reduction of stenoses by administration of nitrates 35 or use of provocative maneuvers 36,37 provides evidence for arterial spasm. Indeed, thrombosis may beget vasospasm. Local thrombus formation generates serotonin, thromboxane A 2 , and thrombin.

Each of these thrombosis-associated mediators can cause vasoconstriction not only at the site of thrombosis, but also downstream. In this manner, a proximal thrombus in an epicardial conduit coronary artery might propagate spasm to the distal smaller vessels. Thrombi present a more tractable therapeutic target than vasoconstriction, as vasodilator drugs, when given systemically, seldom overcome the effect of locally produced constrictor substances.

Growing evidence indicates that in ACS, elevated circulating inflammatory markers, in particular C-reactive protein CRP , predict an unfavorable course, independent of the severity of the atherosclerotic or ischemic burden. Thus, inflammation represents one potential novel pathophysiological mechanism of the ACS that may furnish such a new target for therapy.

Such elevations correlate with in-hospital and short-term adverse prognosis 40—47 and may reflect not only a high prevalence of myocardial necrosis, ischemia-reperfusion damage, or severe coronary atherosclerosis but also a primary inflammatory instigator of coronary instability. The contribution of each of the inflammatory processes mentioned above to prognosis may vary in different groups of patients according to the criteria used for their selection. In turn, the short-term prognostic role of elevated CRP values in ACS may correlate at least in part with the long-term prognostic role of CRP values within the normal range in normal individuals 48,49 and of elevated values in chronic coronary disease.

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Liuzzo et al 41 demonstrated early on that elevated CRP correlates with adverse short-term prognosis in selected patients with unstable angina, Braunwald class IIIb, who lacked evidence of myocardial necrosis and had an ischemic burden similar to that of patients without CRP elevation. Half of patients with ACS have persistently elevated CRP after discharge, a finding associated with recurrent episodes of instability and infarction. Rossi et al, unpublished data, Not all patients with unstable angina and elevated CRP develop infarction.

But practically all patients with infarctions preceded by unstable angina have elevated CRP on admission.


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The final sustained coronary occlusion leading to infarction may result from a coexistent prothrombic diathesis or from enhanced coronary vasoreactivity. In addition, aspects of the acute-phase inflammatory response may directly influence thrombosis. Although CRP serves as a convenient marker of inflammation, the other proteins augmented during the acute-phase response include fibrinogen and plasminogen activator inhibitor Thus, inflammation can promote thrombus formation and can enhance clot stability by inhibiting endogenous fibrinolysis. In patients with ACS, the prevalence of a primary inflammatory pathogenic component of coronary instability, as detectable by elevated CRP, varies considerably.

The increase in CRP and IL-6 observed in response to the vascular trauma caused by coronary angioplasty or by uncomplicated cardiac catheterization 51 and that observed after acute infarction 57 correlates linearly with baseline CRP and IL-6 levels. In vitro, the IL-6 production by isolated monocytes from unstable patients with elevated CRP and IL-6 significantly exceeds that produced by monocytes from patients with normal values. The above discussion reviewed the role of inflammatory mediators and markers in ACS. However, inflammation contributes across the spectrum of cardiovascular disease, including the earliest steps in atherogenesis.

This recognition has had a profound impact on our understanding of atherothrombosis as more than a disease of lipid accumulation, but rather as a disorder characterized by low-grade vascular inflammation. Practically, we can use this concept to predict future cardiovascular risk. The best human data relating inflammation to the prospective development of vascular events have come from large-scale, population-based studies. To date, elevated levels of several inflammatory mediators among apparently healthy men and women have proven to have predictive value for future vascular events.

These observations have considerable importance because, as discussed above, adipocytes can produce inflammatory cytokines, and a common underlying disorder of innate immunity may well link obesity, accelerated atherosclerosis, and insulin resistance. For clinical purposes, the most promising inflammatory biomarker appears to be CRP, a classical acute-phase marker and a member of the pentraxin family of innate immune response proteins.

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Unlike upstream cytokines, CRP has a long half-life, affording stability of levels with no observable circadian variation. These reported functions include an ability to bind and activate complement, induce expression of several cell adhesion molecules as well as tissue factor, mediate LDL uptake by endothelial macrophages, induce monocyte recruitment into the arterial wall, and enhance production of MCP More than a dozen population-based studies have demonstrated that baseline CRP levels predict future cardiovascular events.

CRP testing may thus have a major adjunctive role in the global assessment of cardiovascular risk. In one recent overview analysis that included cases with an average follow-up of 8 years, individuals with basal CRP levels in the top third exhibited a 2-fold increase in future vascular events even after adjustment for all other available vascular risk factors. Download figure Download PowerPoint Figure 2.

Prospective studies of high-sensitivity CRP as a risk factor for future vascular disease. Studies cited are the following: Kuller et al, 66 Ridker et al, 48,49,53,68 Tracy et al, 67 Koenig et al, 70a Danesh et al, 69 Roivanen et al, 70b and Mendall et al. Figure 3. Interactive effects of CRP and lipid testing as determinants of cardiovascular risk. Adapted from Ridker. In addition to providing a simple method to assess low-grade inflammation and improve global risk prediction, CRP screening may also provide a novel method of targeting statin therapy, particularly in the primary prevention of myocardial infarction and stroke.

Both experimental and clinical outcome data now support the hypothesis that statins, in addition to being potent LDL-lowering agents, also attenuate plaque inflammation and influence plaque stability. Both pravastatin and cerivastatin can reduce macrophage content within experimental atherosclerotic plaques, 83—85 whereas simvastatin, fluvastatin, and atorvastatin appear to reduce intimal inflammation 86 and suppress the expression of tissue factor and matrix metalloproteinases both in vivo and in vitro. The first data to link the utility of CRP as a marker of inflammation with potential utility in targeting statin therapy emerged from the Cholesterol and Recurrent Events CARE trial, a secondary prevention study in which elevated CRP levels correlated with significantly increased risk of recurrent coronary events.

The CARE investigators also reported that random allocation to pravastatin lowered CRP levels in a manner unrelated to the effect of pravastatin on LDL or HDL cholesterol, data that provided strong evidence that statins may have important anti-inflammatory effects. Although initially controversial, clinical studies with cerivastatin, lovastatin, simvastatin, and atorvastatin have since replicated the reduction in CRP first described in the CARE trial for pravastatin.

This effect was seen as early as 12 weeks median reduction in CRP with pravastatin As observed in prior hypothesis-generating studies, there was minimal evidence of association between change in LDL cholesterol and change in CRP, data again demonstrating the independent nature of these two effects.

Although provocative, data describing CRP reduction with statins does not in itself establish a role for CRP testing as an adjunct to lipid screening, or as a tool to improve targeting of statin therapy. However, lovastatin therapy also reduced coronary event rates among those with lower levels of LDL cholesterol and above-median levels of CRP. In fact, the event rate in the placebo group as well as the magnitude of risk reduction associated with lovastatin use for those with above-median CRP levels and below-median lipid levels was just as high as that observed among those with overt hyperlipidemia.

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First, they confirm that elevated CRP levels strongly predict future vascular risk and that the addition of CRP to lipid screening helps to predict global risk. Our understanding of atherosclerosis has evolved beyond the view that these lesions consist of a lifeless collection of lipid debris. Current evidence supports a central role for inflammation in all phases of the atherosclerotic process. Substantial biological data implicate inflammatory pathways in early atherogenesis, in the progression of lesions, and finally in the thrombotic complications of this disease.

Clinical studies affirm correlation of circulating markers of inflammation with propensity to develop ischemic events and with prognosis after ACS. Intralesional or extralesional inflammation may hasten atheroma evolution and precipitate acute events. Circulating acute-phase reactants elicited by inflammation may not only mark increased risk for vascular events, but in some cases may contribute to their pathogenesis.

This new insight into the role of inflammation in the pathobiology of atherosclerosis has initiated important new areas of direct clinical relevance. We can use inflammatory markers today for risk stratification. Future studies will gauge their utility as guides to monitor therapy.

Finally, the quest to identify proximal stimuli for inflammation, as one pathogenic process in atherogenesis or trigger to lesion complication, may yield novel therapeutic targets in years to come. Home Circulation Vol. View PDF. Tools Add to favorites Download citations Track citations Permissions. Jump to. Paul M. Ridker Paul M. Abstract Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response.

Download figure Download PowerPoint. Adapted from Ridker et al. E-mail plibby rics. An atherogenic diet rapidly induces VCAM-1, a cytokine regulatable mononuclear leukocyte adhesion molecule, in rabbit endothelium.

Estrogens, lipids and cardiovascular disease: no easy answers.

In the last years, inflammation has emerged as an additional key factor in the development of atherosclerosis and seems to be involved in all stages, from the small inflammatory infiltrate in the early lesions, to the inflammatory phenotype characterizing an unstable and rupture-prone atherosclerotic lesion [4].

In fact, today atherosclerosis is regarded as a disorder characterized by a status of non-resolved inflammation, with bidirectional interaction between lipids and inflammation as a major phenotype. Inflammation in atherosclerosis leads to activation of endothelial cells, enhanced expression of adhesion molecules, inflammatory cytokines and macrophage accumulation. Liver is the main organ regulating lipid metabolism, affecting blood lipids, especially plasma triacylglycerols TAG [5]. Recently, investigators have suggested that the liver plays a key role in the inflammatory state of an individual [6] , [7] , and that dietary cholesterol absorbed by the liver contributes to inflammation [8].

Research into atherosclerosis has led to many compelling discoveries about the mechanisms of the disease and together with lipid abnormalities and chronic inflammation, oxidative stress has a crucial involvement in the initiation and progression of atherosclerosis [9]. Improvement of life style and dietary habits can reduce some risk factors such as high levels of low density lipoprotein LDL -cholesterol, TAG and inflammatory molecules [10]. Fish consumption is consider health beneficial as it lowers plasma lipids and attenuates inflammation [11].

However, fish protein is a rich source of bioactive peptides with valuable nutraceutical and pharmaceutical potentials beyond that of n-3 PUFAs [11]. Fish protein hydrolysates are generated by enzymatic conversion of fish proteins into smaller peptides, which normally contain 2—20 amino acids. In recent years, fish protein hydrolysates have attracted much attention from food scientists due to a highly balanced amino acid composition, as well as the presence of bioactive peptides [12].

The organic acid taurine is mainly found in marine proteins, and is suggested to induce cholesterol-lowering effect by increasing excretion through bile, thus potentially exerting an anti-atherosclerotic effect [13]. Recent studies show TAG-lowering effects [14] , [15] , antioxidant capacity [12] , antihypertensive [11] and cholesterol-lowering effects [16] , [17] , and potential to reduce markers of reactive oxygen species [18] from fish protein. Therefore, fish protein hydrolysates have been implicated in several processes with potential anti-atherogenic effects.

The study was conducted according to national D. After 1 week of acclimatization under these conditions, mice were randomly divided into two groups of 12 mice. The SPH was produced by enzymatic hydrolysis from salmon by-products spine using controlled autolysis with an alkaline protease and a neutral protease, and the resulting protein hydrolysate was then subjected to a second enzymatic treatment with an acid protease A. The final hydrolysate was fractionated using micro- and ultra- filtration and the size distribution of the peptides was analysed.

Other diet ingredients were from Dyets. During the treatment period, blood samples were collected at day 1 and after 77 days from the retro-orbital plexus into tubes containing 0. Aorta was rapidly dissected from the aortic root to the iliac bifurcation, periadventitial fat and connective tissue was removed as much as possible. An equal subset of hearts and all livers were immediately snap-frozen in liquid nitrogen for subsequent analyses.

An operator blinded to dietary treatment quantified the atherosclerotic plaques. Every fifth slide was fixed and stained with hematoxylin and eosin Bio-Optica, Milano, Italy to detect plaque area. Plaque area was calculated as the mean area of those sections showing the three cusps of the aortic valves. Adjacent slides were stained to characterize plaque composition. A biotinylated secondary antibody was used for streptavidine-biotin-complex peroxidase staining Vectastain Abc Kit, Vector Laboratories, Peterborough, UK. A blinded operator to the study quantified plaque area, extracellular matrix and lipid deposition, as well as inflammatory cell infiltrate.

The amount of extracellular matrix, lipids, macrophages and T-lymphocytes was expressed as percent of the stained area over the total plaque area. Total plasma fatty acid composition was analyzed as previously described [20]. Total cellular RNA was purified from 20 mg liver, total homogenized heart and pooled aorta samples from six mice using the RNeasy kit and the protocol for purification of total RNA from animal cells and fibrous tissue Qiagen GmbH, Hilden, Germany , as described by Vigerust et al.

The primers used are listed in Table S2. Livers were homogenized and the post-nuclear fraction isolated as described earlier [23]. The assay for carnitine palmitoyltransferase CPT -2 was performed according to Bremer [24] and Skorve et al. Palmitoyl-CoA oxidation was measured in the post-nuclear fraction from liver as acid-soluble products [26]. The results are presented as mean with standard deviation SD for 4—12 mice per group.

Normal distribution was assessed by the Kolmogorov-Smirnov test. At sacrifice, the average weight gain was 5. A significantly lower plaque development was observed in the aortic arch in SPH-fed mice compared to control mice 0. There were no differences in thoracic 1. After 12 weeks of dietary treatment, whole aorta was collected and en-face analysis was performed to quantify aortic surface covered by atherosclerotic plaques. A significant reduction in lesion area was observed at the aortic sinus of mice fed SPH compared to controls 1.

Plaque stability is an important factor concerning the severity of atherosclerosis. Representative photomicrographs and quantification of maximum plaque area panels A—C. The amount of extracellular matrix, lipids, macrophages and T-lymphocytes is expressed as percentage of the stained area over the total plaque area. Inflammation and oxidative stress are strong contributing factors in atherosclerosis, thus gene expression of inflammatory markers and redox regulators in aorta and heart were measured.

Accompanied by decreased plaque area in sinus and aortic arch, mRNA level of intracellular adhesion molecule Icam1 was decreased with In contrast, no changes were found in gene expression in the heart of Icam1 , Vcam1 , Mcp1 , Nos2 or Tnfa , nor of the antioxidant markers superoxide dismutase 1, soluble Sod1 , superoxide dismutase 2, mitochondrial Sod2 or catalase Cat data not shown. A The gene expressions of the inflammatory markers Icam1 , Vcam1 , Nos2 and Mcp1 were measured in pooled aortic arch from six mice.

To further elucidate the potential anti-inflammatory effects of SPH in this experimental model of atherosclerosis, we examined plasma levels of inflammatory mediators. As shown in Fig. Hyperlipidemia is closely linked to atherosclerotic development. B and C in Figure S1.

ACAT activity, involved in cholesteryl ester synthesis, was also unaltered Fig. D in Figure S1. In order to evaluate the effect of SPH treatment on plasma lipid concentration, blood was collected for enzymatic measurement of lipid profile after 77 days of dietary treatment. As shown in Table 1 , plasma total- and free-cholesterol, as well as TAG, cholesteryl esters and phospholipids concentrations displayed comparable levels between SPH-group and control group at the end of treatment period, whereas NEFAs increased in SPH-fed mice vs.

Moreover, no difference was observed between the two groups in the relative amount of saturated fatty acids SFA Table 2. Overall, the effect of the SPH-diet on plasma lipids and fatty acids was modest. Fish intake is inversely correlated to CVD-risk factors in both observational and clinical interventional trials [28]. Particular attention has been drawn to the cardio-protective effects of fatty fish species with high levels of omega-3 PUFAs through their lipid-lowering, anti-inflammatory, antiplatelet and antiarrhythmic mechanisms [29] , [30].