[Metalloproteinases: therapeutic target in atherosclerosis]. / Les métalloprotéases: cibles thérapeutiques dans l'athérosclérose.

Matrix metalloproteinases are a family of enzymes which collectively can cleave all components of the extracellular matrix. In physiological situations, the expression of matrix metalloproteinases is very low. The increase of their expression leads to several diseases as atherosclerosis, restenosis, rheumatoid arthritis and cancers. In atherosclerosis, metalloproteinases are implicated in the rupture of the atheromatous plaque and contribute to acute vascular accident. Consequently, several studies hypothesized that the inhibition of matrix metalloproteinases activity could reduce the volume of the atheromatous plaque and prevent its destabilisation and therefore could be useful in the treatment of atherosclerosis. However, clinical results have so far been inconclusive because matrix metalloproteinases inhibitors are not very specific. The development of selective inhibitors and gene transfer approaches may better suit the treatment of atherosclerosis.

Plasma metalloproteinase-12 and tissue inhibitor of metalloproteinase-1 levels and presence, severity, and outcome of coronary artery disease.

Several matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the development and outcome of coronary artery disease (CAD). We investigated whether MMP-12 and TIMP-1 levels were associated with risk, severity, and outcome of CAD. Plasma MMP-12 and TIMP-1 levels are measured in 50 and 44 patients with CAD, respectively, by enzyme-linked immunosorbent assay. Of all patients, 16 were taking statins. Patients who were not on statins were classified into 3 groups according to number of >50% stenotic vessels. Compared with 29 volunteers without CAD, patients without statins (n = 34) had higher MMP-12 concentrations (1.71 vs 1.08 ng/ml, p = 0.021). MMP-12 levels were significantly lower in patients with than in those without statin treatment (0.99 vs 1.71 ng/ml, p = 0.008). There was no association between MMP-12 levels and number of >50% stenotic vessels. MMP-12 concentrations were not associated with outcome of CAD. However, plasma TIMP-1 levels were associated with restenosis independently of number of stenotic vessels and age (p = 0.035) but not with risk or severity of CAD. In conclusion, plasma MMP-12 concentration was associated with the presence of CAD. Statin therapy decreases plasma MMP-12 levels in patients with CAD. Increased TIMP-1 levels may prevent restenosis after angioplasty.

Effect of genetic polymorphism +294T/C in peroxisome proliferator-activated receptor delta on the risk of ischemic stroke in a Tunisian population.

PPARδ +294T/C polymorphism was investigated in diabetics, in normolipidemic healthy controls, in dyslipidemic and nondyslipidemic coronary artery disease patients but never in ischemic stroke patients. The aim of this study was to explore, for the first time, the relationship between the genetic polymorphism of PPARδ and the risk of ischemic stroke among patients with diabetes. The study group consisted of 196 patients with ischemic stroke and 192 controls. Plasma concentrations of total cholesterol, triglycerides, low-, and high-density lipoprotein did not differ significantly between subjects carrying the TT genotype and those carrying the CC/TC genotype in both ischemic stroke patients (with or without diabetes) and control groups. The +294C allele (CC + CT genotypes) as compared with TT genotypes was found to be higher in total ischemic stroke patients than in controls. On the other hand, no interaction between diabetes and PPAR +294T/C polymorphism on the risk of ischemic stroke was found (p = 0.089). The PPARδ +294T/C polymorphism was associated with the risk of ischemic stroke in Tunisian subjects. This polymorphism has no influence on plasma lipoprotein concentrations and body mass index either in healthy subjects or in ischemic stroke patients with or without diabetes both in males and females.

Matrix metalloproteinase-1 and matrix metalloproteinase-12 gene polymorphisms and the outcome of coronary artery disease.

OBJECTIVES: In this study, we investigated the association between matrix metalloproteinase-1 (MMP-1) G-1607GG, MMP-12 A-82G and MMP-12 A1082G genotypes and haplotypes and the prognosis of coronary artery disease (CAD). METHODS: A total of 129 Tunisian patients with CAD were followed prospectively for a median of 2.5 years. Genotypes were determined by a PCR-based restriction fragment length polymorphism. Two endpoints were considered: restenosis and incidence of clinical vascular events (restenosis, myocardial infarction, stroke, cardiac death). RESULTS: Genotypes of MMP-1 G-1607GG, MMP-12 A-82G and MMP-12 A1082G were not associated with the incidence of restenosis or clinical events. Analysis of haplotypes consisting of alleles of MMP-1 G-1607GG and MMP-12 A1082G showed that the rate of clinical events was significantly higher in patients carrying the GG-A haplotype than those with other haplotypes (0.637 vs. 0.424, respectively, odds ratio=1.45; 95% confidence interval=1.04-2.04; P<0.05; P adjusted for multiple risk factors). However, after Bonferroni correction for multiple comparisons, this difference did not reach statistical significance (P=0.093), showing that there was a tendency for the association between the GG-A haplotype and future clinical events in patients with CAD. CONCLUSION: These findings showed a trend of the GG-A haplotype of MMP-1 G-1607GG/MMP-12 A1082G towards the prediction of future clinical events in patients with CAD and suggested a possible importance of these loci in the prediction of the prognosis of CAD. Studies with large sample size are warranted to better investigate this association, as MMP genotyping could aid in identifying patients who are likely to have unfavourable prognosis.