Lifestyle comprises various components possibly related to the advancement of atherosclerosis or cardiovascular disease in consequence of atherosclerosis. To elucidate the influence of each component of lifestyle on the risk of the development of cardiovascular disease, we have investigated a signifiant impact of alcohol intake, tabacco smoking, nutrient intake and job strain on the occurrence of cardiovascular disease by reviewing the epidemiologic studies which have been nation or worldwide reported. Some prospects were conducted as an important issue for prevention of cardiovascular disease of the Japanese.
Habitual alcohol drinking raises blood pressure and possibly induces hypertension. Heavy drinking conferres the risk of hemorrhagic as well as ischemic stroke through this mechanism. Small or moderate amounts of alcohol may protect coronary heart disease probably due to elevating high density lipoprotein cholesterol (HDL-cholesterol). Tabacco smoking is a strong risk factor for coronary heart disease even for the Japanese which has been considered as a low cholesterol population. HDL-cholesterol may also be preventive of atherosclerosis, and moderate alcohol drinking and physical activity were proved to increase HDL-cholesterol level, and tabacco smoking decreased it in the cross-sectional observation of epidemiology. The nutrient intake for the Japanese is recently suggested to be a similar pattern to that for the western population, that is more intake of animal fat and protein, and more percent intake of saturated fatty acids. Meanwhile, the prevalence of obesity, glucose intolerance and hypercholesterolemia tended to increase among the recent Japanese population. This leads us to the assumption that multiple risk factors clustering syndrome (Syndrome X or Deadly quartet) is accumulating in the population, and also cardiovascular disease for the Japanese will change from hypertensive pattern to atherosclerotic in the future. Although job strain and psychological stress were reported to be related to the incidence of cardiovascular disease in the Swedish or American epidemiologic studies, ther are a few evidence in the Japanese prospective study. A large cooperative study should be needed throughout the Japan when the complicated social problems in Japan are taken into account. We emphasize an importance of modification of lifestyle for the primary preventive strategy of cardiovascular disease for the Japanese as conclusive remarks.

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Transgenic mouse is a good animal model to study functions of specified gene and its relationship to human disease. We established two transgenic mouse models which overexpress either lipoprotein lipase (LPL) or apolipoprotein (apo) E to study roles of those proteins in lipoprotein metabolism. LPL is an N-linked glycoprotein secreted by various extrahepatic tissues, mainly from muscles and adipose tissue. The secreted enzyme is anchored to the luminal surface of capillary endothelium, and hydrolyzes triglycerides in both chylomicrons and very low density lipoproteins (VLDL), determining the rate of production of low density lipoproteins (LDL) in plasma. The LPL transgenic mice had 5-fold higher LPL activity in adipose tissue. Overexpression of LPL enhanced hydrolysis of triglyceride-rich lipoproteins and lipolytic conversion of VLDL to LDL, and overexpression of LPL acted to protect against diet-induced hyper-triglyceridemia as well as hypercholesterolemia. ApoE, as well as apoB100, is a major component of mammalian lipoproteins and functions in metabolism of plasma lipoproteins through its interaction wiht LDL receptor mainly in the liver. ApoE is also thought to be a specific ligand for putative hepatic chylomicron remnant receptor (apoE receptor). In transgenic mouse lines with integrated rat apoE gene under control of metallothionein promotor, the plasma level of rat apoE in homozygotes for the transgene was 17.4mg/dl after zinc induction. Overexpression of apoE enhanced the clearance of lipoproteins containing apoB100, resulting in reduced plasma cholesterol and triglycerides levels and inhibited diet-induced hypercholesterolemia. Thus, LPL, and apoE plays a key role in diet-related lipoprotein metabolism.

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The earliest lesion of atherosclerosis is characterized by migration of monocyte/macrophages into the subendothelial space and subsequent conversion to foam cells. We have previously shown that LDL modified by cigarette smoke (CS) extract accelerates foam cell transformation of macrophage. In the present paper, we demonstrate that CS-extract could also convert HDL into a form which is less active in stimulation of cholestero efflux from the macrophage-derived foam cells. Incubation with CS-extracts caused denaturation of apoAI and a marked decrease in the effect of HDL on cholesterol efflux from foam cells: the removal of cholesterol from the cells by CS-HDL was 68% of that by native HDL (p<0.05). Superoxide dismutase (SOD) suppressed CS-modification of HDL by 52% (p<0.05). These results taken together suggest that cigarette smoke oxidants including superoxide anion could convert both LDL and HDL into forms that facilitate foam cell transformation of macrophage. It must be determined in the future whether these findings are relevant to accelerated atherosclerosis in the smokers.

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We evaluated the content of EGF, PDGF-AB, b-FGF, and TGF-/β₁ contents and the growth-promoting activity for human vascular smooth muscle cells (VSMC) in platelet lysates obtained from 49 patients with noninsulin-dependent diabetes mellitus and from 23 clinically healthy controls. Platelets were collected from platelet rich plasma and lysed by six cycles of freezing and thawing. Both EGF and PDGF content in platelet lysates in diabetic patients significantly exceeded that of control subjects. There was a significant correlation between the EGF content in platelet lysates and urinaryalbumin excretion or the duration of diabetes. Growth-prompting activity for VSMC in platelet lysates in diabetic patients with hypertension significantly exceeded that of control subjects. The mechanism for the increase of EGF, PDGF and growth promoting activity in platelets remains unclear.

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We clarified, using computed tomography, that the accumulation of intra-abdominal visceral fat is more closely associated with complications of obesity, such as diabetes mellitus, hyperlipidemia, hypertension and ischemic heart disease, than the accumulation of subcutaneous fat. Recently we also revealed that the accumulation of intra-abdominal visceral fat correlates to metabolic disorders and cardiovascular disease even in normal weight subjects. From these backgrounds, we proposed the concept of “visceral fat syndrome”, a multiple risk factors-clustering syndrome for the incidence of atherosclerosis. Clinically, it was showed that the reduction of visceral fat should be important for the cure and the protection of these disorders. We have suggested that physical exercise reduced accumulated visceral fat prominently from the observations of the effect of exercise therapy on visceral fat type obesity and the analysis of fat distribution of sumo wrestlers. In order to clarify the effect of exercise on fat distribution, the mRNA levels and the activities of acyl-CoA synthetase (ACS), lipoprotein lipase (LPL), and glucose transporter (Glut 4) in some tissues were compared between exercised and sedentary rats. We observed rapid decrease of tissue weight in visceral fat through marked decrease of ACS, LPL, and Glut 4 parameters, while there were no alterations of them in subcutaneous fat. Gastrocnemius muscle was heavier in exercised rats, and ACS activity elevated in the gastrocnemius muscle of the exercised rats. By analyzing the expressed genes in human visceral fat, compared with human subcutaneous fat and various tissues, visceral fat was showed to have a higher metabolic activity at fene expression level. We suggest that intra-abdominal visceral fat may contribute to switching of distribution of plasma energy flux, including lipid and glucose, from fat tissue to muscle in physical exercise, in rapid response to exercise from transcriptional level.

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The effects on collagen-induced platelet aggregability of administration of Isbogrel, an inhibitor of thromboxane A₂ synthetase, were investigated on 13 patients with ischemic cerebrovascular diseases and one patient with angina pectoris.
Blood samples were drawn in the morning before breakfast, twice before and once 90 minutes after oral administration of isbogrel. Furthermore, to determine the effect of vessels on platelet aggregebility, rat vessels treated or not treated with aspirin were added to plateletrich plasma for measurement of platelet aggregebility.
Isbogrel markedly suppressed collagen-induced platelet aggregability. The rate of suppression of platelet aggregability was higher with addition of aspirin-treated or non-aspirin-treated vessels than without vessel addition.
The present findings suggest that isbogrel is markedly effective in preventing thrombus formation in vivo.

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In a multicenter trial of Simvastatin treatment, 49 patients with hypercholesterolemia received the drug orally at 5mg once a day after dinner for 12 months.
The plasma concentrations of total cholesterol and low densityl lipoprotein (1.006∼1.063mg/ml, ultracentrifugation) decreased by 24.7±11.2% and 31.0±8.9%, respectively.
The high density lipoprotein cholesterol levels initially below 40mg/dl tended to increase, although those initially over 40mg/dl did not change significantly.
The plasma concentrations of apoB and apoE decreased markedly but those of apoA1, A2, C2 and C3 did not change. The plasma Lp (a) concentration decreased monthly and the maximum rate of decrease was 35±28.4%.
Lipoprotein lipase activity decreased 6M after drug administration but after 12M it increased to the initial level.
The LDL-cholesterol/apoB ratio decreased markedly, suggesting that LDL molecular size was reduced.
No clinical adverse effects were observed in the 49 cases and general chemical examination showed an increase in GPT value from 23 U to 43 U in one case following a continuous course. The abnormal value was eventually normalized.

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