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Verh K Acad Geneeskd Belg. 2008;70(3):193-219.

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

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  • 1Atherosclerose en Metabolisme Eenheid, Departement Hart- en Vaatziekten, KULeuven, Campus Gasthuisberg, Herestraat 49-B 3000 Leuven.

Abstract

The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease. We showed for the first time that the metabolic syndrome is associated with a higher fraction of oxidized LDL and thus with higher levels of circulating oxidized LDL. Hyperinsulinemia and impaired glycaemic control, independent of lipid levels, were associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high oxidized LDL. High levels of oxidized LDL were associated with increased risk of future myocardial infarction, even after adjustment for LDL-cholesterol and other established cardiovascular risk factors. This association is in agreement with the finding that accumulation of oxidized LDL, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production, was associated with upstream localization of a vulnerable plaque phenotype. Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress and impaired HDL-associated antioxidant defence associated with accelerated atherosclerosis due to increased macrophage infiltration and accumulation of oxidized LDL in the aorta. The accumulation of oxidized LDL was partly due to an impaired HDL-associated antioxidant defence due to a decrease in PON. Our data in this experimental model are thus the more relevant because a decrease in PON activity was found to be associated with a defective metabolism of oxidized phospholipids by HDL from patients with type 2 diabetes. Weight loss in leptin-deficient, obese, and insulin-resistant mice was associated with expressional changes of key genes regulating adipocyte differentiation, glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. We established an important relationship between PPAR-gamma and SOD1 for the prevention of the oxidation of LDL in the arterial wall. For example we showed that rosuvastatin decreased the oxidized LDL accumulation by increasing the expression of PPAR-gamma and SOD1. In addition, we established a relation between increased PPAR-alpha expression in the adipose tissue and a change in the gene expression pattern, which explains the decrease of free fatty acids, triglycerides and the increase in insulin sensitivity. We demonstrated that plaque oxidized LDL correlated with coronary plaque complexity in a swine atherosclerosis model. Oxidized LDL correlated positively with the expression of IRF1 and TLR2 suggesting a relation between oxidative stress and inflammation in coronary atherosclerotic plaques. Oxidized LDL induced further the expression of TLR2 and IRF1 in macrophages in vitro suggesting a causative link. As in the mouse model described above, plaque oxidized LDL correlated negatively with SOD1 expression and ox-LDL inhibited the expression of SOD1 in macrophages in vitro. We showed that TLR2, CXCR4 and MYC are overexpressed in monocytes of obese women at high cardiovascular risk and that weight loss was associated with a concomitant decrease of their expression. This suggests that the transcription factor cMYC has an atherogenic effect by inducing pro-inflammatory genes. The increased expression of TLR2 and CXCR4 were observed in the absence of an increase in ox-LDL but in the presence of an increase in SOD1. Interestingly, the expression of SOD1 correlated also with that of MYC, suggesting that it has an atherogenic effect by inducing the expression of an anti-oxidant enzyme. How ox-LDL prevents this increase remains to be determined. How we plan to do this is explained in the next part. In aggregate, our studies contributed to a better understanding of the relationships between metabolic syndrome, insulin signalling, oxidative stress and inflammation and atherosclerosis. We identified paraoxonase, interferon regulatory factor-1, toll-like receptors, CXCR4 and SOD1 as possible targets for intervention.

PMID:
18669160
[PubMed - indexed for MEDLINE]
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