Gamma-glutamyltransferase (GGT), regarded as a marker of excessive alcohol consumption or liver disturbances, is an enzyme catalyzing the first step in the extracellular degradation of the antioxidant glutathione (GSH) and may take part in atherogenesis. The marked relationship between GGT and the atherosclerotic process has shifted attention to the issue of whether its serum levels can aid in the detection of individuals at high risk for incident cardiovascular events. It is likely that the process entails the oxidation of low-density lipoprotein through GSH/GGT-dependent iron reduction within the plaque. In this context, oxidative stress is a probable mediator. Recent insights into the pathophysiological background of GGT in the precipitation and progression of atherosclerosis appear to be supported by relevant epidemiological observations as a cardiovascular risk predictor. Further understanding is, nevertheless, warranted to ameliorate the prognostic stratification of patients through GGT.

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Aim: Serum high molecular weight (HMW) adiponectin improves insulin sensitivity, and a decreased level of serum HMW adiponectin has been reported as a risk factor for the development of diabetes and coronary heart disease. This association may be further confounded by the hemoglobin status, which is involved in the development of atherosclerosis.
Methods: A cross-sectional study was carried out in 2002. Study participants, consisting of 897 men aged 61±14 (mean±standard deviation) years and 1,148 women aged 63±12 years, were randomly recruited from a single community at the time of their annual health examination.
Results: Serum HMW adiponectin levels were lowered dose-dependently with an increased hemoglobin level. Stepwise multiple linear regression analyses for serum HMW adiponectin revealed that the hemoglobin status was independently and significantly associated with serum HMW adiponectin levels as well as sex, age, body mass index (BMI), alcohol consumption, total cholesterol, triglycerides, high density lipoprotein cholesterol, antilipidemic medication, uric acid, serum gamma glutamyltransferase, and insulin resistance. Inclusion of hemoglobin levels in the model further increased the coefficient of determination. In stratified analysis, mean serum HMW adiponectin levels were significantly and similarly decreased as hemoglobin levels increased in men, ages ≥ 65 years, BMI < 23.0 kg/m², alcohol drinkers, and lower insulin resistance, and there were significant interactions between the two groups for BMI, alcohol consumption and insulin resistance.
Conclusion: Hemoglobin status is inversely associated with serum HMW adiponectin levels in community-dwelling persons, especially those aged ≥ 65 years, BMI < 23.0 kg/m², alcohol drinkers, and lower insulin resistance groups.

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Aim: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormone-sensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity.
Method: We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels.
Results: PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity.
Conclusions: The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity.

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Aim: Diabetic peripheral artery disease (PAD) is prone to be aggressive and recent reports have demonstrated that p53 accumulation may be responsible for impaired wound healing in diabetes. Statins has been demonstrated to facilitate p53 degradation by activating its specific ubiquitin ligase, MDM2. The aim of this study was to determine whether atorvastatin (ATR) improves the outcome of diabetic PAD through MDM2-mediated reduction of p53.
Methods: Male KK/Ay mice (9 weeks old) were treated with ATR (2 mg/kg/day p.o.) or vehicle for 2 weeks and subjected to ischemic hindlimb operation to generate a diabetic PAD model. Incidences of amputation and changes of p53/MDM2 signaling in each ischemic limb were assessed 2 weeks after the operation (at 13 weeks of age). Effects of ATR on the insulin resistance of age-matched (13-week-old) and unoperated KK/Ay mice were assessed by the glucose tolerance test, circulating adiponectin concentration, and changes in insulin signaling (IRS-1/Akt phosphorylation).
Results: In intact KK/Ay, ATR treatment mitigated insulin resistance without affecting cholesterol levels. All diabetic PAD models exhibited autoamputation (100%); however, ATR treatment partially restored the limb loss (41.7%). The p53 expression level in the ischemic limb of ATR-treated KK/Ay was significantly decreased and MDM2 phosphorylation level was markedly increased in tandem with the activation of Akt. Hypoxia mimetic iron chelator deferroxamine promoted p53 accumulation in H9c2 myoblast cells by suppressing the Akt/MDM2 pathway, which was restored by ATR.
Conclusions: ATR was found to restore ischemic limb loss in diabetes by augmenting p53 degradation through direct activation of the Akt/MDM2 pathway in skeletal muscle.

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Aim: Whether clusterin/apolipoprotein J is antiatherogenic or proatherogenic is controversial. We reported that clusterin was markedly induced in media and neointima after vascular injury and that reduced clusterin expression reduced the proliferation of vascular smooth muscle cells (VSMCs), which induced G1 arrest via p53 and p21. The purpose of this study was to investigate the physiological function of clusterin in atherosclerosis using double-knockout mice (D-KO) of apolipoprotein E-deficient mice (apoE-KO) and clusterin-deficient mice (CLU-KO).
Methods and Results: Atherosclerotic lesions in the aortic root were quantitated at 20 weeks of age. Atherosclerotic lesions of D-KO were significantly smaller than those of apoE-KO (D-KO: 0.176±0.078 mm² vs. apoE-KO: 0.365±0.164 mm², p< 0.001). To identify underlying atherosclerotic mechanisms that were blocked by loss of clusterin, we performed immunohistochemical analysis of Egr-1. Egr-1 immunoreactivity in the nuclei of VSMCs in atherosclerotic lesions of apoE-KO was upregulated, whereas it was not in D-KO lesions. Western blotting demonstrated that the expression levels of Egr-1 and TNF-α in the D-KO were significantly lower than those in the apoE-KO. When VSMCs and macrophages were obtained from D-KO and apoE-KO, Western blotting showed that the expression levels of Egr-1 and TNF-α in VSMCs and macrophages of D-KO were significantly lower than those of apoE-KO.
Conclusion: Loss of clusterin strongly suppressed apoE-KO-induced atherosclerotic lesions at a step prior to the expression of Egr-1 and TNF-α, suggesting that clusterin is a candidate for an antiatherogenic target.

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Aim: Vascular calcification is a cause of cardiovascular death in hemodialysis (HD) patients. The aim of the present study was to evaluate the relationship between the progression of aortic arch calcification (AoAC) and serum fibroblast growth factor (FGF)-23.
Methods: The enrolled study subjects were 127 (83 men and 44 women) HD patients. Calcification of the aortic arch was semiquantitatively estimated with a score (AoACS) on plain chest radiology. Change in AoACS (ΔAoACS) was obtained by subtracting the baseline AoACS value from the follow-up AoACS value. The second assessment was performed from 5 years after the first determination.
Results: The percentage of male gender in non-progressors (58.5%) was lesser than in regressors (60.0%) and progressors (74.6%). In addition, the dialysis duration in regressors (14.1±5.1 years) was shorter than in non-progressors (19.5±7.0 years) and progressors (16.8±7.5 years). Interestingly, the serum FGF-23 level in regressors (39225.5±9247.9 pg/mL) was significantly higher than in non-progressors (12896.5±26323.5 pg/mL) and progressors (14062.4±18456.8 pg/mL). Multi-ple regression analyses showed male gender (β value=0.969, F=5.092, p=0.0192), serum levels of albumin (β value=−1.395, F=4.541, p=0.0296) and log FGF-23 (β value=−0.001, F=7.273, p=0.0115) to be significant independent determinants of ΔAoACS.
Conclusion: Changes in AoAC evaluated by using a simple chest radiograph are associated with serum FGF-23 levels. Excess accumulation of FGF-23 in serum may enable to inhibit the calcification process in vessel walls in chronic HD patients.

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Aim: Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease (CVD) events. A high ankle brachial index (ABI), a marker of lower arterial stiffness, is associated with CVD events. It remains unknown whether high ABI is associated with CKD. The objectives of this study were to determine the association of CKD with high ABI in adults at high CVD risk.
Methods: The study enrolled hospital-based patients at high CVD risk and measured kidney function and ABI. The glomerular filtration rate (GFR) was estimated using the Modification of Dietin Renal Desease (MDRD) equation and ABI was categorized as low (< 0.90), low-normal (0.90 to 1.09), normal (1.10 to 1.40), and high (≥ 1.40 or incompressible). Logistic regression was used to evaluate the associations of CKD with ABI categories.
Results: Among 6412 participants, 25% had CKD, 25% had an ABI measurement < 0.90, and 1% had an ABI > 1.40. In models adjusted for age, sex, hypertension, diabetes, body mass index, low-density and high-density lipoprotein cholesterol, and smoking, only low ABI was associated with an increased risk of CKD; however, both low ABI (OR: 2.1, 1.6-2.8) and high ABI (OR: 2.4, 1.0-6.4) were associated with an increased risk of CKD in diabetic individuals. Additionally, only low ABI was associated with advanced eGFR levels.
Conclusions: High ABI values are associated with an increased risk of CKD in diabetic individuals at high cardiovascular risk. Future studies are required to speculate whether high ABI might lead to diminished kidney function through nonatherosclerotic pathways and to understand the mechanisms linking them to CVD events and diabetes.

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Aim: The usefulness of drugs to treat plaque regression is assessed by intravascular ultrasound (IVUS); however, the impact of plaque regression on clinical outcomes in patients with acute coronary syndrome (ACS) has not been established; therefore, we investigated the relationship between coronary plaque regression and long-term clinical outcomes.
Methods: We analyzed data from 86 patients who underwent percutaneous coronary intervention (PCI) and who were assessed in detail at baseline and at 6 months of follow-up by measuring proximal non-culprit sites of PCI lesions using volumetric IVUS. Patients were divided according to changes in plaque volume over 6 months into one group with plaque regression (n =55; 64.0%) and another with progression (n =31; 36.0%). They were followed up observationally for a mean of 1,736 days.
Results: Baseline characteristics at the time of ACS were similar between the groups. The probability of event-free survival was significantly higher in the regression group than in the progression group as estimated by the Kaplan-Meier method (Log-rank test, p =0.032). Furthermore, the Cox hazards model revealed the relative contribution of plaque regression as a predictor of cardiovascular events (hazard ratio: 0.26; 95% CI, 0.07 to 0.83; p =0.023).
Conclusions: Plaque regression determined by volumetric IVUS over a period of 6 months was associated with a lower rate of cardiovascular events among patients with ACS. This study also demonstrated that plaque regression could be a surrogate marker of future cardiovascular events.

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Aim: Obstructive sleep apnea-hypopnea syndrome (OSAS) is associated with atherosclerotic cardio-vascular disease. We reported recently daytime hypoadiponectinemia and nocturnal falls in circulating adiponectin concentrations (Δadiponectin) in OSAS patients, in part due to hypoxic stress. The present study investigated the association between Δadiponectin and fat distribution in OSAS males, and the effect of hypoxic stress on adiponectin production in obese yellow-KKAy mice.
Methods: The participants in this study were 43 Japanese males who visited the clinic and were newly diagnosed with OSAS. Venous blood samples were collected before sleep and after wakingup. We investigated the effect of hypoxia on adiponectin expression in mesenteric and subcutaneous fat tissues of obese yellow-KKAy mice. We measured adiponectin secretion into media under hypoxic conditions in an ex-vivo model of yellow-KKAy mice.
Results: In OSAS males with a relatively higher body mass index (BMI), Δadiponectin correlated inversely with the waist-hip ratio, but not with BMI, waist circumference or hip circumference. In obese yellow-KKAy mice, exposure to hypoxia for 2 days suppressed plasma adiponectin levels, with no apparent change in mesenteric and subcutaneous fat tissue adiponectin mRNA expression. In an ex-vivo study of obese yellow-KKAy mice, hypoxic stress reduced adiponectin in the supernatant of mesenteric fat tissues, but not subcutaneous fat tissues.
Conclusions: These findings suggest that abdominal obesity, representing abundant mesenteric fat tissue susceptible to hypoxic stress, partly explains Δadiponectin in OSAS patients, and that reduction of visceral fat accumulation may combat OSAS-related atherosclerotic cardiovascular diseases in abdominal obesity.

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Aim: Cardiorespiratory fitness (CRF) is independently associated with a reduced risk of cardiovascular disease. Carotid arterial remodeling, which is derived from the interplay between carotid luminal dilation and wall thickening, is also an independent predictor of cardiovascular events. We hypothesized that high CRF may be associated with reduced age-related carotid arterial remodeling. This cross-sectional study was performed to determine the relationships between CRF and age-related luminal dilation and wall thickening.
Methods: A total of 771 adults (180 men and 591 women), under age 40 (young), 40-59 (middle-aged), and over age 60 (older) participated in this study. Subjects in each age category were divided into either high (fit) or low (unfit) CRF groups based on VO_2peak. Carotid artery intima-media thickness (IMT) and lumen diameter were measured on ultrasound images. Carotid wall mass was calculated as ρL(πRe²-Ri2).
Results: Two-way ANOVA indicated a significant interaction (p < 0.01) between age and CRF in determining IMT, lumen diameter, and wall mass. In older subjects, IMT, lumen diameter, and wall mass were significantly lower (p < 0.05) in the fit than in the unfit group (IMT, 0.69±0.01 vs. 0.74±0.01 mm; lumen diameter, 5.99±0.06 vs. 6.28±0.06 mm; wall mass, 7.41±0.25 vs. 8.71±0.25 mm³). Multiple regression analysis indicated that the value of VO_2peak was independently correlated with carotid IMT, lumen diameter and wall mass.
Conclusion: The present study indicated that a high level of CRF is associated with reduced agerelated wall thickening and luminal dilation in the carotid artery.

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