Aim: There have been few studies on the relationships of the dietary polyunsaturated to saturated fatty acid ratio (P/S) to cardiovascular risk factors and metabolic syndrome. We hypothesized that there would be favorable relationships.
Methods: Metabolic cardiovascular risk factors from dietary nutrient intake were investigated in 1,004 men and women aged 40-59 years from 4 population samples of Japanese. Multiple linear regression analysis was used to examine the relationship of the dietary P/S ratio to the following risk factors: hemoglobin A1c, blood pressure, serum triglycerides, LDL and total cholesterol, and HDL-cholesterol. Adjusted odds ratio of having metabolic syndrome was also calculated.
Results: The dietary P/S ratio was significantly and inversely related to serum total and LDL cholesterol with control for possible confounding variables. We did not find any significant relationship between the P/S ratio and single metabolic risk factors or the prevalence of metabolic syndrome.
Conclusions: Managing the P/S ratio is important to control serum LDL-cholesterol; however, increasing the P/S ratio may not improve metabolic risk factors. Other countermeasures, such as weight control, greater physical activity, and smoking cessation should be recommended to prevent and control metabolic syndrome.

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Aim: It has been shown that the calcium antagonist nifedipine upregulates superoxide dismutase (SOD). Although the peroxisome proliferator-activated receptor (PPAR) response element is located in the promoter region of Cu/ZnSOD, it remains unclear whether nifedipine upregulates PPARs and inhibits vascular remodeling. We hypothesthized that nifedipine activates PPARγ, inhibits vascular remodeling, and improves vascular function in hypertension.
Methods: Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with vehicle, nifedipine, and PPARγ selective antagonist GW9662 with nifedipine.
Results: Systolic blood pressure in the three SHRSP groups was higher (p <0.01), and the left ventricular weight/body weight ratio was greater (p <0.01) than in the Wistar-Kyoto rat (WKY) group with no differences observed among the three SHRSP groups. In the SHRSP heart, nifedipine significantly inhibited intramyocardial arterial remodeling and perivascular fibrosis, and reduced oxidative stress, while it significantly restored adiponectin and the smooth muscle cell (SMC) phenotype, and selectively restored PPARγ and Cu/ZnSOD expression/activities to their levels in the WKY rat heart. Furthermore, nifedipine induced a dose-dependent increase in PPARγ expression in cultured vascular SMCs. These effects of nifedipine were completely abolished by the co-administration of GW9662 with nifedipine. Nifedipine treatment significantly improved acetylcholine-induced relaxation by 27% compared with the vehicle SHRSP group, but it was still significantly impaired by 20% compared with the WKY group.
Conclusions: Nifedipine may inhibit vascular remodeling and improve vascular function by selective activation of PPARγ through the activation of Cu/ZnSOD in hypertension.

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Aim: The aim of our work was to determine the influence of intestinal bacteria on the development of atherosclerotic lesions using apolipoprotein E (ApoE)-deficient knockout mice.
Methods: The experiments were performed on ApoE-/--deficient mouse strain C57BL/6, bred under germ-free (GF) conditions for two generations or under conventional conditions with defined microflora (CV). The mice were fed a standard low cholesterol diet or cholesterol-rich diet for 3-4 months. We studied the development of advanced lesions in the thoracic and abdominal aorta by histological, morphometric and immunohistological methods.
Results: Conventionally reared ApoE-/- mice (containing no pathogenic intestinal microbiota) and fed a standard low cholesterol diet in contrast to a high cholesterol diet did not develop atherosclerotic aortic plaques. In contrast, ApoE-/- mice reared under germfree conditions for 2 generations and fed a low cholesterol diet exhibited atherosclerotic plaques in the aorta. Characteristic lipid deposition with foam cells and macrophages was found in their arterial walls.
Conclusion: In contrast to the absence of atherosclerotic plaques in conventionally reared ApoE-deficient mice, germ-free ApoE-/- mice consuming the same low cholesterol standard diet developed atherosclerotic plaques in the aorta. Differences in atherosclerotic plaques between GF and CV ApoE-/- mice are not so apparent when mice are fed a high cholesterol diet. Our findings thus document the protective effect of microbiota (commensal bacteria) on atherosclerosis development.

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Aim: To examine the efficacy and safety of prostaglandin E₁ incorporated into lipid microspheres (lipo-PGE₁), Palux® Injection, in patients with diabetic foot ulcers classified as ischemic, neuropathic, or neuroischemic at 108 medical institutions throughout Japan.
Methods: A prospective observational study.
Results: The safety and efficacy of the drug were analyzed in 388 and 280 patients, respectively.The overall ulcer size reduction rate at the end of administration was 42.5%: 34.0%, 61.8%, and 33.1% in 71 patients with ischemic ulcer, 70 patients with neuropathic ulcer, and 125 patients with neuroischemic ulcers, respectively. Although lipo-PGE₁ was effective for all the ulcer types examined, the ulcer size reduction rate was significantly higher for neuropathic ulcer than for other types of ulcers. The overall change in the ulcer severity score was -6.1. The change rates in ulcer severity scores were -5.5, -8.4, and -5.2 for ischemic, neuropathic, and neuroischemic ulcers, respectively. The overall efficacy rate was 71.5%. The efficacy rate for neuropathic ulcer was 83.6%, which was significantly higher than for ischemic (68.8%) and neuroischemic (65.3%) ulcers. On the other hand, the incidence of adverse drug reactions was 4.1% (16 cases among 388 patients), indicating that the drug was well tolerated.
Conclusion: Lipo-PGE₁ can be administered relatively safely for diabetic foot ulcers and is effective for all the ulcer types examined, especially for neuropathic ulcer.

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Aim: Cigarette smoking is a major risk for developing atherosclerosis; however, the underlying mechanism is poorly understood. This paucity of knowledge is largely attributed to the lack of an animal model; therefore, our efforts were targeted towards establishing cigarette smoke (CS)-induced atherosclerosis in guinea pig. To understand the mechanism, we investigated apoptosis, an event implicated in atherosclerosis, in the aorta of CS-exposed animals. Since a major deleterious effect of CS is oxidative stress, we also examined the effect of vitamin C, an antioxidant, on CS- induced atherosclerosis.
Methods and Results: Guinea pigs on a diet with or without vitamin C supplement were exposed to CS for different time periods. Aortal sections from these animals were examined for atherosclerotic changes by staining with H&E and Oil red O. Atherogenic changes were observed in sections obtained from CS-exposed guinea pigs only. TUNEL assay showed the occurrence of apoptosis in CS-exposed guinea pig aorta. Our results revealed that CS-induced apoptosis could contribute to the progression but not to the initiation of the disease. Immunohistochemical analysis documents that CS-induced apoptosis in aortal sections is mediated at least in part by an increased Bax/Bcl2 ratio. In contrast, CS-exposed guinea pigs fed with vitamin C-supplemented diet exhibit little or no atherogenic changes. This anti-atherosclerotic activity of vitamin C can be attributed partly to its ability to inhibit CS-induced apoptosis and platelet activation.
Conclusion: Exposure of guinea pigs to cigarette smoke causes the development of atherosclerosis, which can be prevented by vitamin C supplement.

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Aim: The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on randomized controlled trial.
Methods: Thirty-eight type 2 diabetic patients (21 men and 17 women) were assigned to either the exercise group (n=21) or the control group without exercise training (n=17) by simple randomization. The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months. After the 3-month, we investigated endothelial function, insulin resistance, adipocytokines and inflammatory markers. The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation (FMD). Furthermore, we followed the incidence of cardiovascular events for 24 months.
Results: After 3-month, HbA1C was decreased significantly in both groups. FMD was increased from 7.3±4.7% to 10.9±6.2% only in the exercise group (p<0.05). Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group (p<0.05).
Conclusions: Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes. The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months.

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Aim: The aim of this study was to investigate whether environmental endocrine-disrupting chemicals, bisphenol A (BPA) and BPA-related chemicals, affect adiponectin production and secretion in 3T3-L1 adipocytes and whether BPA acts through Akt signaling.
Methods: 3T3-L1 adipocytes were treated for 24 h with BPA at various concentrations (20-80μM) in serum-deprived medium. The medium was filtered through a 0.2μm filter. Adiponectin in the infranatants of cell homogenates and in the media was measured using an adiponectin ELISA kit. The levels of Akt and p-Akt in cultures treated for 24 h with or without 80μM BPA were analyzed by Western blot.
Results: The control cultures (i.e., BPA was absent during a 24-h treatment period) contained 49.4μg/mg DNA of adiponectin in the cells and secreted 35.5μg/mg DNA of adiponectin into the medium. BPA at 80μM dose-dependently decreased the amounts of intracellular and medium adiponectin by 60% (p<0.01) and 56% (p<0.01), respectively, and decreased the levels of Akt and p-Akt by 46% (p<0.01) and 29% (p<0.01), respectively, compared with the control cultures. Like BPA, bisphenol F (BPF), bisphenol E (BPE), and bisphenol B (BPB) decreased the amounts of intracellular and medium adiponectin. The order of the potential to decrease the amount of intracellular adiponectin was BPB>BPA>BPE>BPF.
Conclusions: BPA downregulates Akt signaling and inhibits adiponectin production and secretion in 3T3-L1 adipocytes.

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Aim: Modified low-density lipoprotein (mLDL), mainly upon oxidative and enzymatic modification, is the major atherogenic lipoprotein. Conversely, high-density lipoprotein (HDL) is considered antiatherogenic because of its ability to remove cholesterol. The aim of this work was to analyze both the influence of HDL on the uptake of mLDL and the expression of CD36 and Fcγ I receptors on monocytic cell lines during cell differentiation.
Methods: Uptake of fluorescein isothiocyanate (FITC)-conjugated LDL and FITC-conjugated mLDL, i.e., copper-oxidized LDL (oxLDL) or trypsin enzyme modified LDL (enzLDL), was analyzed, as well as the expression of CD36 and FcγRI in THP-1 and U937 cells, using flow cytometry.
Results: HDL inhibited the uptake of mLDL, which varied in degree depending on the cell line or type of mLDL. Further, HDL rapidly decreased CD36 and FcγRI involved in the uptake of mLDL.
Conclusions: We demonstrate that modified LDL promotes specific LDL receptor-independent uptake by monocytic cell lines, and that the uptake of LDL and enzLDL is less than that of oxLDL. In this process, HDL diminishes the uptake of LDL or mLDL, which may involve the down-regulation of receptors (CD36 and Fcγ I). This regulatory process represents another way by which HDL can be anti-atherogenic and it depends on the type of modification of LDL and the stage of differentiation of monocytes to macrophages.

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Aims: Despite the clinical usefulness of transcutaneous oxygen tension (TcPO₂) to assess the severity of limb ischemia, the factors determining TcPO₂ in patients with peripheral arterial disease (PAD) have not been fully clarified. We therefore examined the regions of arterial stenosis and clinical factors affecting lower-extremity TcPO₂.
Methods: Resting TcPO₂ (REST-TcPO₂) and postexercise TcPO₂ (Ex-TcPO₂) in the calf region and the dorsalis pedis were measured simultaneously in 66 patients (132 limbs) with clinically suspected PAD, in whom angiography was also performed.
Results: The peripheral arteries of the lower extremities were divided into five segments, and the impact of significant stenosis in each segment on ipsilateral TcPO₂ was evaluated by multiple regression analysis. In the calf region, significant stenosis of the proximal arteries (common-external iliac artery) revealed stronger involvement determining Ex-TcPO₂ than the peripheral segment (posterior tibial artery). In the dorsalis pedis, the peripheral segment (anterior tibial artery) more strongly determined Ex-TcPO₂ and REST-TcPO₂ than proximal segments. Age, creatinine, and diabetes were associated with REST-TcPO₂ of the calf region independent of arterial stenoses, while those of the dorsalis pedis were independently associated with age, and creatinine. In contrast, Ex-TcPO₂ in both regions was not independently associated with clinical factors, except for stenosis of the perfusing arteries.
Conclusion: The vascular lesions affecting TcPO₂ differ between the calf region (proximal > peripheral) and the dorsalis pedis (proximal < peripheral). In addition postexercise TcPO₂ is solely determined by stenosis of the perfusing arteries, while TcPO₂ at rest is affected by multiple clinical factors.

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Aim: Since we previously reported that lower levels of HDL-C may be most useful for predicting coronary artery disease (CAD) as assessed by multi-detector row computed tomography (MDCT), we sought to confirm, among the levels of LDL-C, HDL-C, non-HDL-C (total cholesterol minus HDL-C) and the ratio of LDL-C to HDL-C (LDL-C/HDL-C), which is most closely related to the presence of CAD.
Methods and Results: The subjects consisted of 506 consecutive patients with suspected CAD who underwent MDCT with (+) or without (-) statin treatment. The levels of LDL-C in the statin (-) group were similar in categories I, II and III according to the Japan Atherosclerosis Society (JAS) Guidelines 2007, whereas the levels of HDL-C significantly decreased and LDL-C/HDL-C signifi-cantly increased as the category number increased. In the statin (-) group, the prevalence of CAD in categories I, II and III was 0, 16 and 33%, respectively (p=0.0018 for trend), in patients with good control of LDL-C levels according to the Guidelines. Multivariate logistic regression analysis was per-formed to examine the association between the presence of CAD and 11 possible factors. Age and HDL-C in the statin (-) group, and HDL-C in the statin (+) group were identified as significant independent variables that correlated with the presence of CAD. Receiver-operating characteristic curve analysis in the statin (-) and statin (+) groups showed a higher area under the curve for HDL-C than for LDL-C, non-HDL-C or LDL-C/HDL-C. In particular, the cut-off levels of HDL-C with the greatest sensitivity and specificity for the diagnosis of CAD in the statin (+) group were 55 mg/dL (sensitivity 0.816, specificity 0.510).
Conclusions: HDL-C levels are most closely associated with the presence of CAD. In particular, we need to perform coronary CT for suspected CAD patients with lower HDL-C levels under statin treatment.

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Aims: To evaluate the relationship between low-density lipoprotein cholesterol (LDL-C) change and reduction of cardiovascular disease in the Management of Elevated cholesterol in the primary prevention Group of Adult Japanese (MEGA) study.
Methods: Patients in the diet plus pravastatin group were divided into tertiles by their on-treatment LDL-C level, and the hazard ratios (HRs) in each tertile were compared with the diet group at 5 years using the Cox proportional hazards model. In addition, the treatment groups were combined and divided into quintiles according to the on-treatment LDL-C level during follow-up, and the incidence of cardiovascular events was compared among the 5 groups.
Results: In the tertiles of the diet plus pravastatin group, HR was lowest in the second tertile against the diet group (HR 0.57, p=0.01) with on-treatment LDL-C range of 119.8-133.4 mg/dL. In the analysis of quintiles of the total population, a significant risk reduction of CVD was found in the fourth quintile (HR 0.48, p=0.0015) with an on-treatment LDL-C range of 120.9-133.3 mg/dL, and in the fifth quintile (HR 0.64, p=0.048) with an on-treatment LDL-C range of 56.7-120.8 mg/dL against tertile 1 with an on-treatment LDL-C range of 157.5-206.2 mg/dL.
Conclusions: The usual Japanese dose of pravastatin therapy is sufficient in this low-risk patient population to reduce cardiovascular risk, with an achieved LDL-C level <133.4 mg/dL. Further risk reduction was not found with an achieved LDL <120 mg/dL.

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