Aim: To examine the association between renal vasculature changes and generalized atherosclerosis using autopsy cases.
Methods: We histologically examined 107 autopsy patients(mean age, 68.4 years; 64% men; 81% non-CVD) to investigate the association between renal vasculature changes and generalized atherosclerosis. We measured the intima/media(I/M) ratio for the renal, intrarenal and systemic arteries(coronary, cerebral, common carotid and common iliac), calculated the rates of arteriolar hyalinization and global glomerulosclerosis and evaluated the frequency of advanced lesions(AHA classification ≥IV) in the systemic arteries.
Results: The I/M ratios of the renal and intrarenal arteries and the rate of global glomerulosclerosis increased with age, while the rates of arteriolar hyalinization and global glomerulosclerosis were associated with diabetes and hypertension(all p＜0.05). The I/M ratio of the coronary artery was independently associated with the rate of global glomerulosclerosis(p＜0.05). The frequency of advanced atherosclerotic lesions in the coronary and cerebral arteries was also correlated with the I/M ratio of the renal artery and rates of arteriolar hyalinization and global glomerulosclerosis(all p＜0.05). The frequency of advanced lesions in the cerebral and common carotid arteries was independently associated with the I/M ratio of the renal artery and the rate of renal arteriolar hyalinization(odds ratio(OR) with [95% confidence interval]; 5.09 [1.15-27.9] and 4.11 [1.38-13.9], respectively).
Conclusions: The results of this study demonstrated that pathological changes in four portions of the renal vasculature differ. Renal vasculature changes except the intrarenal arteries were significantly associated with those observed in the cerebral, common carotid and coronary arteries.

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Aim: Resveratrol(RSV) is an edible polyphenolic phytoalexin present in different plant species that plays an important role in improving endothelial dysfunction. However, the molecular mechanisms underlying these effects are unknown. In the present study, the mechanism underlying the protection of CRL-1730 cells by RSV against oxidative stress was examined.
Methods: We first assessed the effects of RSV on the cell viability and apoptosis of CRL-1730 cells exposed to hydrogen peroxide(H₂O₂). Real-time PCR was used to determine the microRNA-126(miR-126) expression in cells treated with RSV and/or H₂O₂. We also evaluated the PI3K/Akt signaling pathway in CRL-1730 cells following upregulation of the miR-126 expression. Finally, we determined the effects of miR-126 on RSV against oxidative injury using an miR-126 inhibitor.
Results: Treatment with RSV resulted in a significant increase in survival and a decrease in the apoptosis of CRL-1730 cells exposed to H₂O₂. We also found that H₂O₂ significantly suppressed the expression of miR-126, which was reversed by RSV in a dose-dependent manner. The overexpression of miR-126 decreased PIK3R2(p85-β) and enhanced Akt phosphorylation, which resulted in an increase in the survival of CRL-1730 cells exposed to H₂O₂. More importantly, the downregulation of the miR-126 expression reversed the effects of RSV on the survival and apoptosis of CRL-1730 cells exposed to H₂O₂. In addition, the knockdown of Ets-1 reversed the effects of RSV on the miR-126 expression in CRL-1730 cells exposed to H₂O₂.
Conclusions: In this study, we demonstrated that the protection of endothelial cells by RSV against oxidative injury is due to the activation of PI3K/Akt by miR-126.

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Aims: The protective effects of hawthorn fruit against atherosclerosis and the potential underlying mechanisms of this fruit in improving the hypolipidemic and antioxidant activities were investigated in apolipoprotein E-deficient(apoE^−/−) mice.
Methods: ApoE^−/− mice were divided into a control group(n=10) and hawthorn fruit group(n=10). The mean size of the lesions in the aortic root was assessed, and the serum glucose levels, insulin levels, lipid profiles, total antioxidant capacity(T-AOC) and superoxide dismutase(SOD) and glutathione peroxidase(GSH-PX) activities were measured. The mRNA levels of hepatic genes related to lipid metabolism and antioxidant enzymes were examined.
Results: The hawthorn fruit group mice developed significantly decreased(p＜0.05) atherosclerotic lesions. The levels of serum lipids decreased significantly(p＜0.05) and the levels of cholesterol/triglycerides, including very-low-density lipoprotein(VLDL) and low-density lipoprotein(LDL), decreased in the hawthorn fruit group. The hawthorn fruit mice exhibited significantly increased T-AOC values and SOD and GSH-PX activities(p＜0.05). The hepatic fatty acid synthase(FAS) and sterol regulatory element binding protein-1c(SREBP-1c) mRNA levels were reduced by 42%(p＜0.05) and 23% p＜0.05) in the mice fed the hawthorn fruit diet compared with that observed in the mice fed a standard diet. However, the hepatic hydroxymethylglutaryl CoA reductase(HMG-CoAR) mRNA levels showed no significant differences between the two groups. The mRNA expression levels of the antioxidant enzymes(SOD1, SOD2, Gpx3) were higher(p＜0.05) in the livers of the hawthorn fruit diet mice compared with those observed in the control mice.
Conclusions: Hawthorn fruit exerts a protective effect against atherosclerosis in apoE^−/− mice by improving the hypolipidemic and antioxidant activities.

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Aims: The association between an elevated serum neopterin level and the development of coronary artery complex lesions has been extensively assessed; however, the correlation between the serum neopterin level and the development of carotid artery stenosis has seldom been reported. This study tested whether this biomarker is increased in patients with severe carotid artery stenosis(≥70%) undergoing carotid artery(CA) stenting and investigated independent predictors of an increased circulating neopterin level.
Methods: Fifty patients with severe CA stenosis(CAS) undergoing CA stenting were consecutively enrolled in this study from January 2009 through December 2011. The serum neopterin levels of age- and gender-matched acute ischemic stroke(AIS) patients(n=120) and control subjects(CS)(n=33) were also measured. A blood sample was prospectively collected from each patient in the catheterization room.
Results: The serum levels of neopterin were significantly higher in the CAS patients than in the AIS patients or CS and significantly higher in the AIS patients than in the CS(all p＜0.001). An analysis of the variables of 170 patients(CAS＋AIS) demonstrated that age, a previous history of stroke and severe CAS were significantly correlated with an increased serum level of neopterin(all p＜0.005). A multivariate binary logistic regression analysis of the severe CAS patients(n=50) demonstrated that age and the creatinine level were independent predictors of a high neopterin level(neopterin level ≥16.52 ng/dL, i.e., according to the median value of neopterin)(all p＜0.05).
Conclusions: The circulating neopterin levels are significantly higher in patients with severe CAS than in those with AIS. The presence of CAS, age and the creatinine level were significantly correlated with an increased serum neopterin level.

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Aim: To compare the responsiveness to clopidogrel in patients who were prescribed two different types of statins, atorvastatin vs. rosuvastatin, following percutaneous coronary intervention.
Methods: A total of 915 patients were randomized according to the antiplatelet therapy strategy in the CILON-T trial. In this subgroup analysis, we included patients who took atorvastatin(20 mg/day, n=295) or rosuvastatin(10 mg/day, n=261) during the entire study period and underwent measurement of the P2Y12 reaction unit(PRU) values at both discharge and six months. We compared the P2Y12 reaction unit(PRU) values at six months and investigated the relationship between the genotypes of cytochrome P450(CYP) 3A4, 3A5 and 2C19 with the PRU values at six months in both groups.
Results: The baseline characteristics did not differ between the groups. There were no significant differences in the PRU values at discharge(atorvastatin 221.0±87.3 vs. rosuvastatin 217.1±84.7, p=0.59). However, the rosuvastatin group had higher PRU values than the atorvastatin group at six months(atorvastatin 226.4±79.3 vs. rosuvastatin 241.5±88.2, p=0.033). In the genotype analysis, the number of CYP2C19 loss-of-function (LOF) alleles(^＊2 or ^＊3) was positively associated with a higher PRU value in both statin groups, and there were no significant interactions regarding the PRU values between the number of CYP 2C19 LOF alleles and the type of statin(p for interaction=0.56). In the multivariate analysis, the use of rosuvastatin was a significant predictor of a PRU value of ＞273(the highest tertile)(OR 1.67, 95% confidence interval 1.05-2.65, p=0.031).
Conclusions: Rosuvastatin is associated with high on-treatment platelet reactivity compared with atorvastatin following the coadministration of clopidogrel for six months. Further studies are therefore warranted to clarify the mechanism underlying this relationship.

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Aim: The high-density lipoprotein cholesterol(HDL-C) level is a major negative risk factor for atherosclerotic diseases dependent on various lifestyle parameters. Changes in the lifestyle of Japanese individuals over the past several decades is believed to have increased their total cholesterol levels and the incidence of cardiovascular disease in Japan. It is therefore important to assess the long-term trends in the HDL-C levels with respect to public health in the community.
Methods: In this study, accumulated data for the serum/plasma HDL-C levels published in cohort studies and obtained during health checkup programs in Japan were analyzed with respect to timedependent changes.
Results: The levels of HDL-C have continuously and significantly increased over the past 20 years by 12-15% according to the National Health and Nutrition Study, other cohort studies and commercially available data. On the other hand, the non-HDL-cholesterol levels demonstrated no changes or only a slight decrease during the same period. This finding is consistent with several sets of data obtained from health checkup programs. The commercially measured levels of serum apoA-I, an independent parameter of serum HDL, also showed a similar long-term increase, supporting the above findings.
Conclusion: We concluded that the serum/plasma HDL concentrations in Japanese individuals, selectively, have increased continuously and significantly over the past 20 years or more. The reasons for this phenomenon and the consequent public health outcomes have yet to be investigated.

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Aim: It has previously been shown that flow-mediated vasodilation is a predictor of the progression of the intima-media thickness (IMT). In the present study, the degree of endothelium-dependent vasodilation in both resistance and conduit arteries was evaluated as a predictor of the IMT and plaque progression.
Methods: In the population-based Prospective Study of the Vasculature in Uppsala Seniors(PIVUS) trial(1,016 subjects all 70 years of age), the invasive forearm technique using acetylcholine administered in the brachial artery (resistance artery, EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (conduit artery, FMD) were evaluated. The IMT and number of carotid arteries with plaques (0, 1 or 2) were recorded using ultrasound at the baseline investigation and the follow-up visit conducted five years later.
Results: A total of 760 subjects had valid measurements of the IMT and carotid artery plaques at both the investigations conducted at 70 and 75 years of age. Neither the FMD nor EDV significantly predicted the change in IMT over five years. However, the FMD, but not EDV, was associated with the change in carotid plaque burden during the follow-up period, independent of classical risk factors, such as gender, waist circumference, fasting blood glucose, systolic and diastolic blood pressure, HDL- and LDL-cholesterol, serum triglycerides, BMI and smoking (OR 0.81 for a 1 SD change in FMD, 95%CI 0.68 to 0.95, p=0.010).
Conclusions: The FMD was found to be a predictor of changes in the carotid plaque status, but not IMT, during the 5-year follow-up period, independent of classical cardiovascular risk factors.

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