Recent developments in our understanding of the atherosclerotic process and factors that trigger ischemic cardiovascular disease have led to the consideration of antioxidative responses or exogenous antioxidants, which are proposed to inhibit multiple proatherogenic and prothrombotic events in arterial wall. Heme oxygenases (HO), an enzyme essential for heme degradation, have been shown to have such antioxidative properties via the production of bile pigments, carbon monoxide and ferritin induction. We have demonstrated that mildly oxidized LDL markedly induces HO-1, an inducible form of HO, in human aortic endothelial and smooth muscle cell cocultures and that its induction results in the attenuation of monocyte chemotaxis induced by mildly oxidized LDL. We also confirmed abundant expression of HO-1 in human, murine and rabbit atherosclerotic lesions. By modulating HO activities in LDL-receptor knockout mice and Watanabe heritable hyperlipidemic rabbits during their atherosclerotic lesion developments, anti-atherogenic properties of HO have demonstrated as judged by the quantitative analyses of atherosclerotic lesion formation. HO expression was inversely correlated with the levels of plasma and tissue lipid peroxides. HO also influenced on nitric oxide pathway. These observations may suggest that HO, induced during atherosclerotic process, functions as an intrinsic protective pathway in vascular wall. J Atheroscler Thromb, 2001 ; 8 : 63-70.
Spontaneously hyperlipidemic (SHL) mice are Japanese wild mice (KOR) with disruption of the apolipoprotein E (Apo E) gene. These mice (KOR-Apoeshl) are superhypercholesterolemic and develop severe xanthoma, but their atherosclerosis is relatively mild compared with Apo E knockout mice. First, we tested whether this distinction is due to additional mutation of the Apoc1 and/or Apoc2 genes in KOR-Apoeshl. Southern blot analysis, but found no gross disruption of these genes. Next, we tested whether the phenotypic distinction is due to differences in the genetic background. To this end, we established three lines of congenic SHL mice with a genetic background of C57BL/6, BALB/c or C3H/He, and named them, respectively, C57BL/6.KOR-Apoeshl (B6.KOR-Apoeshl), BALB/c.KOR-Apoeshl (C. KOR-Apoeshl) and C3H/He.KOR-Apoeshl (C3.KOR-Apoeshl). Hypercholesterolemia was most severe in KOR-Apoeshl followed the by others as follows ; KOR-Apoeshl>>C3.KOR-Apoeshl> C.KOR-Apoeshl > B6.KOR-Apoeshl. In contrast, atherosclerosis was most severe in B6.KOR-Apoeshl followed by the others : B6.KOR-Apoeshl >C.KOR-Apoeshl> >C3.KOR-Apoeshl≥KOR-Apoeshl. This order, however, did not match that in xanthoma, which was highly prominent in KOR-Apoeshl but mild in B6.KOR-Apoeshl, C.KOR-Apoeshl and C3.KOR-Apoeshl. This order, however, did not match that in xanthoma, which was highly prominant in KOR-Apoeshl but mild in B6.KOR-Apoeshl, C.KOR-Apoeshl and C3.KOR-Apoeshl. These distinctions suggest that the severity of each of the phenotypes is determined by distinct genetic backgrounds which probably are composed of polymorphism of lipid metabolism-related proteins. We found that apolipoprotein A-I is decreased in each SHL strain and polymorphic between B6.KOR-Apoeshl and the other strains examined. This polymorphism may be related to the most severe atherosclerosis observed in B6.KOR-Apoeshl. It is most likely that combination of such polymorphisms is due to the genetic background accountable for phenotype distinctions. J Atheroscler Thromb, 2001; 8 71-79.
To investigate whether the Ala54Thr polymorphism of the fatty acid binding protein 2 gene is associated with obesity and obesity with dyslipidemia in Japanese schoolchildren, we analyzed 370 children with morbid obesity and 463 control children of normal weight. The allele frequencies did not differ significantly between the control group and the morbidly obese group. The odds ratio (95% confidence interval CI) in obesity of the The54 allele was 1.0 (0.9-1.3). There were no significant differences in obesity index and metabolic characteristics between the two groups. The odds ratio (95% CI) in dyslipidemia of the Thr54 allele was 1.1 (0.8-1.4) in the morbidly obese group. Our data suggested that Ala54Thr polymorphism of the FABP2 gene is not a major contributing factor for obesity and obesity with dyslipidemia in Japanese children. J Atheroscler Thromb, 2001 ; 8 : 80-83.
Although ultracentrifugation is the gold standard for lipoprotein analysis, inexpensive and easy direct methods for HDL-and LDL-cholesterol (C) have recently been developed. In this study, we compared representative methods of lipoprotein analysis, namely, ultracentrifugation, direct assay methods, and HPLC, to measure LDL-and HDL-C. A good correlation was observed between HDL-C by ultracentrifugation and HDL-C by direct methods or HPLC. A good correlation was also observed between LDL-C (d1.006-1.063) by ultracentrifugation and LDL-C by direct methods or HPLC. Although the correlation between LDL-C (d1.019-1.063) by ultracentrifugation and LDL-C by direct methods was also good, the correlation coefficient was significantly decreased, suggesting that IDL-C' by direct methods correlates better with LDL-C (d1.006-1.063) than LDL-C (d1.019-1.063) by ultracentrifugation. Although the correlation between IDL-C (d1.006-1.019) by ultracentrifugation and the difference in LDL-C by direct methods and LDL-C (d1.019-1.063) by ultracentrifugation was investigated, no significant correlation was observed. The IDL-C contained in LDL-C (d1.006-1.063) varied from 2-28%. In homozygous CETP-deficient and LCAT-deficient subjects, the dissociation was marked. It is crucial to understand that 'LDL-C' in the Guidelines for the Diagnosis and Treatment of Hyperlipidemias in Adults by the Japanese Atherosclerosis Society should be considered to be LDLC (d1.006-1.063) and that 'LDL-C' by direct assay methods means LDL-C (dt.006-1.063) by ultracentrifugation.
Homocysteine is considered to be an independent risk factor for atherosclerosis. Experimental animal models of hyperhomocysteinemia show aortic calcification, suggesting that this disorder is associated with aortic calcification in humans. A total of 28 patients with hyperlipidemia were enrolled into this study. The degree of aortic calcification at the level of the bifurcation and 1 cm proximal to the bifurcation was assessed by computed tomography of the aorta and the association between calcification of the aorta and the plasma level of homocysteine was then analyzed. The mean plasma homocysteine level in 28 patients was 8.7, μ M. They were divided into 2 groups, high homocysteine level group (HHL ; homocysteine level>8.7, μ M) and low homocysteine level group (LHL ; homocysteine level<=8.7 μ M). The degree of aortic calcification at the level of the bifurcation differed significantly between the two groups (19.1% vs. 10.5% ; p <0.01). We found that mild hyperhomocysteinemia was associated with aortic calcification, which suggests that interventions to reduce the plasma level of homocysteine may also reduce the severity of aortic calcification. J Atheroscler Thromb, 2001 ; 8 : 91-94.
High density lipoprotein-cholesterol (HDL-C) levels are inversely related to the incidence of coronary artery disease. We studied the influence of a G (-75) - > A transition in the promoter of the apolipoprotein (apo) A-I gene, a major protein component of HDL, on serum HDL-C levels in hyperlipidemic subjects. Seventy-three hyperlipidemic subjects with serum levels of high HDL-C (HDL-C 70 mg/dl, Group H) were compared with hyperlipidemic subjects with levels of HDL-C between 40 and 70 mg/dl (Group N) and those with HDL-C < 40 mg/dl (Group L). Group H showed a higher incidence (45.2%) of low plasma cholesteryl ester transfer protein (CETP) activity than Groups N (9.1%) and L (5.3%) (p < 0.001). Group H had a higher incidence of the G (-75) - > A transition (0.275) than Groups N (0.117, p < 0.05) and L (0.056, p < 0.01), among subjects with normal CETP activities. The HDL-C levels in subjects with the transition (84+16 mg/dl) were higher than those in subjects without the transition (56+12 mg/dl) (p < 0.05). These data suggest that a G (-75) - > A transition of the apo A-I gene promoter, in addition to the common mutation of CETP gene, contributes to high HDL-C levels among hyperlipidemic patients in Japan.