No abstract

To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and their tissue inhibitos (TIMPs) in patients with premature coronary atheroscrelosis, we studied 53 consecutive male patients with angiographically defined premature (<65 years) and stable coronary artery disease. Plasma levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 were determined in peripheral blood by a sandwich enzyme immunoassay, and the results were compared with those from 133 age-matched control males. There were significant differences in all the MMPs and TIMPs (p<0.001) between patients and controls. In the patient group, the levels of MMP-9 (mean +/- SD (ng/ml) 27.2 +/- 15.2/21.8 +/- 15.2) and TIMP-1 (130.4 +/- 55.7/94.5 +/- 26.3) were significantly higher, and the levels of MMP-2 (632.5 +/- 191.6/727.6 +/- 171.4), MMP-3 (53.1 +/- 31.2/79.6 +/- 29.9), and TIMP-2 (24.7 +/- 15.2/35.4 +/- 16.4) were significantly lower than those of controls. We found significant positive correlation between plasma MMP-9 levels and low-density lipoprotein (LDL)-cholesterol levels (Rs = 0.168, p = 0.022), and significant negative correlation between plasma MMP-9 levels and high-density lipoprotein (HDL)-cholesterol levels (Rs = -0.164, p = 0.026) by Spearman rank correlation test. In contrast, plasma MMP-2 (Rs = 0.181, p = 0.014) and MMP-3 (Rs = 0.260, p = 0.0004) levels were positively correlated with HDL-cholesterol levels. TIMP-2 levels were negatively correlated with total cholesterol (Rs = -0.197, p = 0.007) and LDL-cholesterol (Rs = -0.168, p=0.022) levels. These results suggest that the circulating levels of MMPs and TIMPs are altered in patients with premature coronary atherosclerosis and that plasma lipoprotein cholesterol levels correlate with these, possibly as a result of the lipoprotein-vessel wall interactions.

The mechanisms responsible for interindividual variation in response to statin therapy remain uncertain. It has been shown that hepatic cholesterol synthesis is associated with ATP binding cassette transporter G5 and G8 (ABCG5/8) activities. To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. In carriers of the D19H variant, means of posttreatment values and adjusted percent reductions in LDL cholesterol (LDLC) were significantly lower ( P ϭ 0.028) and greater ( P ϭ 0.036) (112 mg/ dl, 39.7%) than those of noncarriers (119 mg/dl, 36.2%), respectively, while no significant difference was observed in percent reductions in total cholesterol. Stepwise multiple regression analysis revealed significant and independent associations with absolute or percent reduction between D19H genotype and posttreatment LDL cholesterol levels. The other polymorphisms were not significantly associated with treatment effects. These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy. -Kajinami, K., M. E. Brousseau, C. Nartsupha, J. M. Ordovas, and E. J. Schaefer. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. In hepatocytes, the reduction in cholesterol content, in turn, causes a decrease in the secretion of apolipoprotein B (apoB)-containing lipoproteins and an upregulation of LDL receptor activity, both of which contribute to the reduction in plasma LDL cholesterol (LDLC) levels observed with statin therapy. ATP binding cassette transporters G5 and G8 (ABCG5/8) are unique proteins located in the plasma membrane, as well as in the intracellular membranes of enterocytes and hepatocytes. Mutations in the genes encoding for ABCG5/8 have been identified as the cause of sitosterolemia (9-11), a rare inborn error of metabolism characterized by elevated plasma levels of plant sterols due to hyperabsorption and decreased biliary sterol secretion. Impairment of these pathways results in a decrease of cholesterol biosynthesis in hepatocytes (12, 13), raising the possibility that interindividual variation in plasma cholesterol concentrations (14,15), and possibly the response to statin treatment, is, in part, due to variation in the ABCG5/8 genes.We, and others, have previously shown that apoE genotype is associated with the plasma lipid response to statin therapy (16,17). The present study was undertaken to test the hypothesis that polymorphisms at the ABCG5/8 gene loci are associated with plasma lipid response to statin treatment. SUBJECTS AND METHODSStudy subjects were the same patient group, in which we found the gender-specific effects of apoE genotype on plasma