Relations between metabolic syndrome, oxidative stress

1 downloads 0 Views 312KB Size Report
(63) Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C,. Simmgen M, Clements M, Claret M, Maccoll G, Bedford DC, Hisadome K,. Diakonov I ...
Verh K Acad Geneeskd Belg. 2008;70(3):193-219.

Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. Holvoet P.

Atherosclerose en Metabolisme Eenheid Departement Hart- en Vaatziekten, Katholieke Universiteit Leuven Campus Gasthuisberg, Herestraat 49, 3000 Leuven

RELATIONS BETWEEN METABOLIC SYNDROME, OXIDATIVE STRESS AND INFLAMMATION AND CARDIOVASCULAR DISEASE by

P. HOLVOET Bekroond met Prijs Dr. Karel-Lodewijk Verleysen, periode 2004-2007

INTRODUCTION The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. (1-4) It is a primary risk factor for diabetes and cardiovascular disease (5-13). About 80 % of all type 2 diabetes is associated with insulin resistance. Obesity and insulin resistance, and the interaction between these two components, are associated with a high cardiovascular risk (14;15). Obesity-related type 2 diabetes is a leading cause of morbidity and mortality in Western societies, and is quickly approaching pandemic proportions (16). The prevalence of obesity continues to increase, with more than 50% of Europeans currently classified as overweight and up to 30% as clinically obese (17-19). In the WHO report on integrated management of cardiovascular risk it was estimated that, yearly about a quarter of a million deaths in Europe and more than 2·5 million deaths worldwide are weightrelated, with cardiovascular disease as the leading cause. The recent rapid increase in childhood overweight and obesity will lead to a further increase in prevalence of the metabolic disease and its associated high cardiovascular risk. Although insulin resistance and type 2 diabetes are associated with increased coronary heart disease (CHD), the severity of insulinemia and glycaemia during the diabetic phase can only explain this increased risk to a minor extent. Traditional risk factors do not fully explain this excess risk, and other "non-traditional" risk factors may be important (20). Therefore, the European Innovative Medicines Initiative gives priority to the identification of emerging risk factors that are targets for prevention and treatment. An early abnormality in insulin-resistant states that might contribute to premature atherosclerosis is endothelial dysfunction (21). Activated endothelial cells secrete chemokines and adhesion molecules, which attract monocytes and immune cells (22). Another player in the pathogenesis of insulin resistance and type 2 diabetes, is subclinical chronic low-grade inflammation (20). Population studies show a strong correlation between pro-inflammatory biomarkers (such as C-reactive protein, interleukin-6, and tumour necrosis factor- ) and perturbations in glucose homeostasis, obesity, and atherosclerosis (23;24). Adipocytes could contribute to this chronic low-grade inflammation by producing proinflammatory adipokines.

1

Obesity is also associated with increased infiltration in the adipose tissue of monocytes/macrophages, which produce inflammatory chemokines and increase oxidative stress (25). Diabetes is associated with the activation of circulating monocytes, which have an increased ability for attachment to normal endothelial cells and infiltration in the vascular wall. This increased infiltration is a primary stage in atherogenesis (26). Finally, recent data suggest that increased oxidative stress in accumulated fat is an early instigator of the metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for the obesityassociated metabolic syndrome (27). The important role of obesity is further evidenced by the fact that weight loss is associated with a decrease of the cardiovascular risk of insulin-resistant obese persons. This is possibly due to changes in the inflammatory and oxidant profile of adipocytes and monocytes in adipose tissue and the circulation, respectively (28). OBJECTIVES OF OUR STUDIES The objectives of our studies were: 1) To determine the association between levels of oxidized LDL (ox-LDL), an emerging marker of oxidative stress and cardiovascular risk, with the metabolic syndrome and associated cardiovascular events. 2) To assess the relation between plaque ox-LDL and vulnerable plaque phenotype. 3) To develop a mouse model of the metabolic syndrome allowing the study of mechanisms that link obesity with insulin resistance and diabetes and atherosclerosis with special emphasis on oxidative stress. 4) To identify molecular mechanisms which explain the protective effect of weight loss and statin treatment, for the latter beyond its cholesterol lowering effect. 5) To identify genes in coronary plaque macrophages which explain the relations between oxidative stress, inflammation and atherosclerosis. 6) To identify genes related to oxidative stress and inflammation which correlate with the progression of coronary atherosclerosis, are overexpressed in monocytes of obese persons, and of which the expression decreases after weight loss.

THE METABOLIC SYNDROME IS ASSOCIATED WITH ELEVATED LEVELS OF CIRCULATING OXIDIZED LDL AND HIGH RISK OF MYOCARDIAL INFARCTION Previously, we had demonstrated that in the Health ABC cohort, comprising 3,033 participants aged 70-79 years, ox-LDL was elevated in persons with high CHD risk (according to adjusted Framingham scoring) before any events (29) and that addition of ox-LDL to the established risk factors may improve cardiovascular risk prediction (30). We then demonstrated that the metabolic syndrome in this cohort was associated with a higher cardiovascular risk (31). Therefore, our objective was to establish the association between the metabolic syndrome and oxLDL and to determine the risk for CHD in relation to the metabolic syndrome and ox-LDL. Compared with that of participants without the metabolic syndrome, the odds ratio (OR) for high ox-LDL (>1.90 mg/dl) in participants with the metabolic syndrome was 1.82, after adjusting for age, sex, ethnicity, and smoking status. No interaction with sex and ethnicity was observed. After further adjustment for LDL-cholesterol, the OR was 2.01. When ox-LDL was expressed as the percent of LDL, the adjusted OR for high ox-LDL (>1.58%) was 2.56. Higher waist circumference and levels of triglycerides, insulin, glucose, and HbA1c (adjusted for glucose and insulin), and lower levels of HDL-cholesterol were associated with higher adjusted prevalence of high ox-LDL. No significant association between blood pressure and ox-LDL was observed (32). The prevalence of cardiovascular disease was higher in persons with the metabolic

2

syndrome and higher levels of ox-LDL. This prevalence was the highest in persons with the metabolic syndrome and elevated ox-LDL (Figure 1). We determined the relative risk of myocardial infarction (MI) in relation to the metabolic syndrome and ox-LDL, adjusted for age, sex, ethnicity, and smoking status. Those with the metabolic syndrome had a 2.0-fold higher risk. The incidence rate for those with the metabolic syndrome was 5.6% vs. 2.9% (P < 0.001) for those without the metabolic syndrome. We also divided the cohort into five groups by levels of ox-LDL. The incidence of MI was 5.7% in the highest quintile of ox-LDL compared with 2.6% (P < 0.01) in the lowest quintile. The risk ratio for persons in the highest quintile was 2.25 (95% CI 1.22 4.15). After adjusting for the metabolic syndrome, the risk ratio for persons in the highest quintile of ox-LDL was 1.87 (1.00 3.49). In summary, we have shown for the first time in a population cohort that the metabolic syndrome is associated with a higher fraction of ox-LDL and thus with higher levels of circulating ox-LDL. As expected, dyslipidemia (low HDL-cholesterol and high triglycerides) was associated with high levels of ox-LDL. It had been shown in healthy, non-diabetic volunteers that plasma glucose and insulin levels correlate with a higher susceptibility of ex vivo oxidation of LDL. Here we have shown that hyperinsulinemia and impaired glycaemic control, independent of lipid levels, are associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high ox-LDL. This association was consistent across sex and ethnicity. Our data further support the importance of identifying individuals with the metabolic syndrome as a high-risk group for developing CHD. Finally, our study identified the oxidation of LDL as a potential mechanism explaining the increased risk for MI among those with the metabolic syndrome. Interestingly, we confirmed the relation between the metabolic syndrome components and the increase in circulating ox-LDL in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, and showed that ox-LDL is associated with subclinical CVD by its relation with many cardiovascular risk factors (33). The association between the metabolic syndrome and elevated levels of ox-LDL has been confirmed in European and Japanese cohorts (34-36). In addition, two recent studies showed that levels of circulating ox-LDL predict future cardiovascular events even after adjustment for traditional cardiovascular risk factors and C-reactive protein (37;38).

OXIDIZED LDL ACTIVATES SMOOTH MUSCLE CELLS AND MACROPHAGES TO GELATINASE PRODUCTION AND PLAQUE INSTABILITY The observed association between high ox-LDL and high risk for MI prompted us to further investigate mechanisms through which ox-LDL might decrease plaque stability. The Thorax centre and the Departments of Cell Biology and Genetics and of Vascular Surgery of the Erasmus University Medical Centre Rotterdam developed a new technique that preserved the original intravascular ultrasound derived lumen geometry of dissected and reconstructed aortic vessel segments (39). Together, we demonstrated that the longitudinal distribution of lipid particles, macrophages, and smooth muscle cells (SMCs) in plaques in the infrarenal aorta from hypercholesterolemic rabbits is heterogeneous. Surprisingly, a similar upstream accumulation of gelatinolytic activity and ox-LDL was detected. Distribution of each variable with plaque area revealed a higher accumulation of macrophages upstream compared with that downstream of the plaque. In contrast, a more diffuse distribution of vascular SMC and lipids was measured. As a consequence, the local vulnerability index upstream of maximal plaque area was higher than downstream. This higher vulnerability upstream is similar to observations in the carotid arteries of patients. Inspection of histological cross sections and quantitative analysis revealed that both SMC and macrophages were associated with gelatinolytic activity. Although this pointed to a similar contribution of SMC and macrophages to overall gelatinolytic activity, the fractions associated with gelatinolytic activity represented only a minor fraction of overall macrophage

3

(23±7%) and SMC (22±7%) content. These co-localized with foamy SMC and macrophages which were associated with ox-LDL. In conclusion, the vulnerable plaque phenotype is probably due to an accumulation of oxLDL, which activates/induces subsets of SMCs and macrophages to gelatinase production. The fact that foamy SMC and foamy macrophages are located in similar vessel segments might be explained by the evidence that macrophages secrete factors enhancing uptake of cholesteryl ester by vascular SMC.

INCREASED LDL OXIDATION RESULTS FROM IMPAIRED HDL ANTIOXIDANT DEFENCE As shown above, the metabolic syndrome in humans is associated with increased LDL oxidation. Our next objective was to identify a mouse model of the metabolic syndrome that allowed the study of molecular mechanisms explaining the relations between the metabolic syndrome components and increased oxidative stress. We found that mice with combined leptin (ob/ob) and LDL receptor deficiency (LDLR-/-) are obese and show severe hypertriglycemia, and glucose intolerance, insulin resistance and diabetes. Therefore, we investigated whether increased ox-LDL was associated with accelerated atherosclerosis in these double knockout (DKO) mice. We wanted to define the underlying mechanisms in the case of a positive relation (40). All mice were on standard chow containing 4% fat. Compared with lean mice (C57BL6 and LDLR-/-), both obese ob/ob and DKO mice had higher fasting and non-fasting blood glucose and insulin levels, resulting in similarly increased HOMA (marker of insulin resistance) values. In addition, fasting triglycerides were higher in DKO mice than in any other strain. This combination of insulin resistance and hypertriglycemia resulted in accelerated progression of atherosclerosis due to increased accumulation of macrophages. Correlation between the number of homed macrophages and mean lesion area was 0.85 (Spearman r; P