Both type I and type II MSRs are integral membrane proteins containing a collagenous domain and elicit an extraordinarily wide range of ligand binding capability. They were found during the search for the molecule (s) responsible for the accumulation of modified LDL during atherogenesis. However, all prior the evidence relating to their physiological and pathophysiological roles in vivo had been indirect. Targeted disruption of the MSR gene results in a reduction in the size of atherosclerotic lesions in an apo E deficient animal. Macrophages from MSR deficient mice exhibit a marked decrease in modified LDL uptake in vitro, whereas modified LDL clearance from plasma remains normal, suggesting that there are alternative mechanisms for the uptake of modified LDL from the circulation. In addition, MSR knockout mice are more susceptible to L. monocytogenes and HSV-1 infection, indicating a role for MSR in host defense against various pathogens. J Atheroscler Thromb, 1997 ; 4 : 1-11.

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Since endothelial cells (EC) are known to secrete various anti-proliferative and vasodilating factors, an agent that promotes seeding or regeneration of EC may have potential therapeutic value against vascular smooth muscle cell (VSMC) proliferation. To seek an endothelium-specific growth factor, we have focused on hepatocyte growth factor (HGF). HGF is belonged to a member of endothelium-specific growth factors, whose mitogenic action on EC was most potent among growth factors. Moreover, the presence of local HGF system (HGF and its specific receptor, c-met) was observed in EC and VSMC of rat and human in vitro as well as in vivo. Production of local HGF production in vascular cells was regulated by various cytokines including transforming growth factor (TGF) -β and angiotesin II (Ang II). Furthermore, HGF may be a therapeutic growth factor for the treatment of restenosis after angioplasty and arteriosclerosis obliterance, etc., as gene therapy. From these characteristics of HGF, we hypothesized that HGF might contribute to the protection or repair of vascular endothelial cells. Indeed, serum HGF concentration was significantly correlated with blood pressure, suggesting that HGF secretion might be elevated in response to high blood pressure as a counter-system against endothelial dysfunction. In this review, we discussed that HGF is a member of the endothelium-specific growth factors whose serum concentration is significantly associated with blood pressure. J Atheroscler Thromb, 1997 ; 4 : 12-16.

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We now have discovered and characterized a novel multi-domain protein and classified it as a member of the LDL receptor gene family. The-250 kDa membrane protein, termed LR11, highly conserved in man, rabbit and chicken, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor “YWTD” repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, liver and adrenal glands. Ligand blotting of LR11-transfected cells demonstrated that LR11 binds apolipoproteinE-containing lipoproteins, as well as other members of LDL receptor gene family. In contrast to the LDL receptor, the mRNA levels in rabbit liver is unaffected by hyperlipidemia. The features of this highly conserved and complex mosaic protein suggest the importance of the ever expanding LDL receptor gene family in the evolution and proposed multifunctionality J Atheroscler Thromb, 1997 ; 4 : 20-26.

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Changes in coagulation and fibrinolysis in the plasma (in vivo) and hepatocytes (ex vivo) were studied using hyperglycemic rats. Hyperglycemia was induced by intravenous injection of 50 mg/kg streptozotocin (STZ). Eight weeks after the injection, we observed increases in thrombin-antithrombin III complex and tissue type plasminogen activator activity, decreases in plasma levels of antithrombin III, plasminogen and α₂-plasmin inhibitor, and significant shortening of activated partial thromboplastin time. In freshly isolated or cultured hepatocytes from STZ-induced hyperglycemic rats, concentrations of proteins related to coagulation were increased. An increase in alanine-aminotransferase leakage and decreases in the levels of amylase, triglycerides and phospholipids were observed in the culture medium of hepatocytes from STZ-treated rats. In vivo study revealed that STZ-induced subchronic diabetes induced imbalance between coagulation and fibrinolysis, and ex vivo study in hepatocytes from STZ-treated rats showed membrane degeneration and reduction in amylase synthesis, while protein synthesis related to coagulation was not inhibited. These results suggest that, despite vulnerability of liver cells from STZ-treated rats, coagulation activity in the liver is retained and rather enhanced in STZ-induced hyperglycemic rats, which may contribute to the promotion of atherosclerosis. J Atheroscler Thromb, 1997 ; 4 : 27-33.

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Spin-echo magnetic resonance imaging (MRI) and postprocessing for fat quantification were used to examine the relationship of abdominal and thigh adipose-tissue distribution to serum lipids and glucose metabolism in obesity. Thirteen simple obese male patients and 12 nonobese male volunteers were examined by MRI, blood pressure, and fasting blood sample levels of serum lipids, glucose, immunoreactive insulin, c-peptide, HbA₁C and hematocrit. Correlations of thigh visceral and subcutaneous fat areas to serum lipid levels were generally similar, but marked differences were found between relationships of thigh versus abdominal fat areas to serum lipid levels. In addition, diastolic blood pressure was significantly correlated with the fat area, especially with the abdominal visceral fat area (r = 0.51, p <0.01), but not with abdominal subcutaneous fat area. The thigh muscle area was highly and inversely correlated with c-peptide (r =-0.72, p< 0.01) and systolic blood pressure (r =-0.65). Differences in correlations between visceral and subcutaneous fat areas in the abdomen to metabolic parameters were found between abdominal visceral fat areas and HbA₁C and between the abdominal subcutaneous fat areas and HbA₁C. These findings suggest that the character of regional fat could be heterogeneous with respect to lipid and glucose metabolism and blood pressure levels in obese males. J Atheroscler Thromb, 1997 ; 4 : 34-39.

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To examine the significance of apolipoprotein E (apo E) polymorphism in the hypolipidemic effect of bezafibrate, we evaluated the influence of different apo E phenotypes on serum lipid response to bezafibrate treatment in 58 dyslipidemic patients with WHO phenotypes of llb, IV, or isolated hypo-HDL cholesterolemia. Patients were categorized into one of three groups according to apo E phenotypes of E2 (E2/3, n = 5), E3 (E3/3, n = 35), and E4 (E3/ 4 and E4/4, n=18). After 3 months daily administration of 400 mg bezafibrate, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels changed on average in the E3 group [-8.0% ; p< 0.05 and +1.1% ; not significant (ns), respectively], the E2 group (-18.3% ; p<0.005 and-26.9%; p<0.05, respectively) and the E4 group (+3.8%; ns and +10.1%; ns, respectively). The changes in TC and LDLC levels in the E4 group was significantly less effective compared with those in the E3 (p < 0.05) and E2 groups (p < 0.01). Bezafibrate induced a reduction in serum triglyceride (TG) levels in the E3 group (-50.1%; p < 0.0001), the E2 group (-46.9% ; p < 0.05) and the E4 group (-44.8% ; p < 0.005). An increase in high-density lipoprotein cholesterol (HDLC) levels was also observed in the E3 group (+ 27.5% ; p< 0.0001), the E2 group (+ 35.0% ; ns) and the E4 group (+ 38.8% ; p< 0.005). However, there was no significant difference in the changes of TG and HDLC levels between the groups. These results suggest an important role of apo E polymorphism in modulating serum lipid response to bezafibrate, and phenotyping of apo E helps predict the therapeutic effect of bezafibrate treatment. J Atheroscler Thromb, 1997 ; 4 : 40-44.

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We describe the development of sandwich enzyme-linked immunosorbent assays designed to measure native and glycated apolipoprotein B-containing particles in plasma. The assays utilize monoclonal antibodies anti native or glycated apo B-LDL for coating and a polyclonal anti apoB-LDL-peroxidase conjugate as the detecting antibody. The method is specific, sensitive and precise. The intra-assay coefficient of variation for the plasma native and glycated apolipoprotein B-containing particles was determine to be 7.8% and 7.5%, respectively. The method described can provide specific and reproducible determinations of apoB and glycated-apoB containing particles in plasma it will be of great interest in the evaluation of atherosclerotic risk in dyslipoproteinemic states in diabetic and nondiabetic subjects.J Atheroscler Thromb, 1997 ; 4 : 45-49.

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