Sir2 (silent information regulator-2), an NAD+-dependent histone deacetylase, is highly conserved in organisms ranging from archaea to humans. Yeast Sir2 is responsible for silencing at repeated DNA sequences in mating-type loci, telomeres and rDNA, and plays critical roles in DNA repair, stress resistance and longevity. The phenomenon of human aging is known to be a critical cardiovascular risk factor. Senescence of endothelial cells has been proposed to be involved in vascular dysfunction and atherogenesis. Recent studies have demonstrated that mammalian Sirt1 NAD+-dependent protein deacetylase, the closest homologue of Sir2, regulates vascular angiogenesis, homeostasis and senescence. This review focuses on SIRT1 as a potential therapeutic target against atherosclerosis.
Numerous large-scale clinical studies have revealed that the low-density lipoprotein cholesterol (LDL-C)-lowering effect of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) prevents coronary heart disease (CHD). Statins have not only LDL-C-lowering effects but also high-density lipoprotein cholesterol (HDL-C)-elevating effects, which differ among statins. In this article, we discuss the molecular mechanisms of HDL-C elevation by statins and its effect on HDL functions. We summarize the reports to date on the effects of statins on various proteins, enzymes and receptors involved in reverse cholesterol transport (RCT), which is one of the protective systems against atherosclerosis. Since statins increase the synthesis of apolipoprotein A-I (ApoA-I) and HDL neogenesis in the liver, the HDL-C-increasing effect of statins may reflect RCT activation. Moreover, HDL has pleiotropic effects, including anti-inflammatory and anti-oxidative effects, as well as RCT. In the future, it may be necessary to assess the functions of HDL elevated by statins, and select statins based on differences in their effects in clinical practice.
Background: It remains unclear how much coronary risk factors contribute to the prediction of myocardial infarction among Japanese populations. Methods and results: A nested case-control study of Japanese male workers aged 35 to 65 years was conducted between 1997 and 2000 in the Morbidity of Myocardial Infarction Multicenter Study in Japan (3M Study). Two hundred four myocardial infarctions were identified and two controls per case were selected by matching for age. We calculated odds ratios using a conditional logistic regression model, and constructed risk predictive models for the risk of myocardial infarction using coronary risk factors. The multivariable odds ratios (95 percent confidence intervals) of myocardial infarction were 2.02 (1.29-3.16) for high blood pressure, 2.33 (1.51-3.59) for high LDL-cholesterol, 4.16 (2.36-7.33) for low HDL-cholesterol, 1.49 (0.94-2.35) for high triglycerides, 1.46 (0.89-2.39) for high glucose, and 2.95 (1.90-4.59) for current smoking. A large reduction of the predictive value for myocardial infarction was shown after exclusion of high LDL-cholesterol (reduction of predictive value was -3.4%), further exclusion of low HDL-cholesterol (-7.1%), and further exclusion of current smoking (-16.4%). Conclusions: High LDL-cholesterol and low HDL-cholesterol as well as current smoking had high predictive values for myocardial infarction among Japanese middle-aged male workers.
Aim: Limited correlations between C-reactive protein (CRP) and coronary artery disease (CAD) have been reported. Recently, MRI became a useful tool for non-invasively evaluating atherosclerotic plaques in thoracic and abdominal aortas. Methods: To elucidate the associations between plasma CRP levels and the severities of coronary and aortic atherosclerosis, we performed aortic black-blood MRI in 136 patients undergoing coronary angiography. For each patient, 9 slices of thoracic aorta and 9 slices of abdominal aorta were obtained at 12-mm intervals, and the plaque extent in each slice was scored. The degree of aortic atherosclerosis is represented as the sum of scores. The degree of coronary atherosclerosis is represented as the number of >50% stenotic vessels and >25% stenotic segments. Results: CAD (>50% stenosis) was present in 96 patients. Patients with CAD had higher CRP levels than those without CAD (median 0.78 vs. 0.48 mg/L, p<0.02). CRP levels tended to increase depending on the number of stenotic vessels: 0.48, 0.70, 0.74, and 0.88 mg/L (p=NS). CRP correlated weakly with the number of stenotic segments (r=0.21). Regarding aortic atherosclerosis, 136 patients were divided into quartiles by plaque score. CRP levels increased stepwise in quartiles: 0.40, 0.56, 1.08, and 1.10 mg/L (p<0.001). CRP levels also correlated with the plaque score (r=0.38). In multivariate analysis, aortic atherosclerosis was an independent factor for CRP levels, but coronary atherosclerosis was not. Conclusion: Plasma CRP levels correlated with the severities of both coronary and aortic atherosclerosis, but CRP levels are more likely to reflect the severity of aortic atherosclerosis than coronary atherosclerosis.
Aim: The purpose of the study was to determine the sensitive cutoff values of waist circumference (WC) in relation to the body mass index (BMI) for detecting the clustering of cardiovascular risk factors (CCRF) in Japanese men and women. Methods: The study population included 2,476 male and female residents who participated in a ward health examination in Tokyo, Japan. The CCRF were defined according to the Japanese Committee of the Criteria for Metabolic Syndrome. Receiver Operating Characteristics (ROC) analysis was conducted within each BMI category. Results: The percentage of study participants in the normal BMI category was around 70% for both men and women. The sensitive cutoff values for the largest WC with at least 80% sensitivity were 81 cm for normal and 89 cm for overweight men. The corresponding values for women were 79 cm and 86 cm, respectively. The WC with maximized sensitivity plus specificity was 80 cm for normal and 89 cm for overweight men, and the sensitivity was 88.7% and 83.0%, respectively. The corresponding values for women were 78 and 94 cm, respectively, and the sensitivity was 91.5% and 57.6%, respectively. Conclusions: For the early detection and management of clusters of cardiovascular risk factors, we concluded that a BMI-specific WC cutoff value of 80 cm for normal weight in both men and women and 89 cm for overweight men and 86 cm for overweight women should be discriminate cutoff values.
Aim: Alcohol intake may increase serum gamma-glutamyltransferase (GGT) but reduce insulin resistance. We analyzed the association between GGT and a marker of insulin resistance, homeostasis model assessment for insulin resistance (HOMA-IR), according to the drinking and smoking status. Methods: After excluding former smokers and/or former drinkers, the data of 10,482 men who underwent general health screening were analyzed. Results: Alcohol consumption showed a graded association with GGT. In men with current alcohol consumption of ≥40 g per day, ≥20 cigarettes per day further increased GGT levels. Alcohol consumption showed a U-shaped association with HOMA-IR. In contrast, smoking 20-39 and ≥40 cigarettes per day increased HOMA-IR as compared with never smokers. An interaction between alcohol consumption and smoking was present for GGT (p<0.001) and HOMA-IR (p=0.059). GGT was not a significant negative predictive value for HOMA-IR regardless of the drinking or smoking status. Conclusions: Although alcohol intake showed a graded association with GGT and a U-shaped association with HOMA-IR, serum GGT can be utilized as a predictor of insulin resistance in current drinkers.
Aim: Metabolic syndrome (MS) comprises a constellation of various metabolic abnormalities, but insulin resistance is considered the basis of the syndrome. The relationship of plasma fibrinogen with MS and insulin resistance remains inconclusive. The aim of this study was to assess whether plasma fibrinogen levels were associated with MS and insulin resistance in a rural population of China. Methods: Participants were selected using a multi-stage random-sampling method. A standardized interview was conducted by trained personnel, and “metabolic syndrome” was defined according to the Chinese Diabetes Association. Insulin resistance was assessed by fasting insulin and HOMA-IR. Associations of fibrinogen levels with components of MS and insulin resistance were determined using correlation analysis and multiple linear regression analyses. Results: A total of 1,792 participants (M: 815, W: 977) aged 15 to 85 years was studied. Adjusted mean fibrinogen concentration increased with increases in the number of MS components (p<0.001). Multiple linear regression analyses showed that fibrinogen concentration was significantly and positively associated with age, DBP and negatively with physical exercise and HDL-C in males and females, and positively with WHR, LogTG, and FPG in females. No statistically significant association between fibrinogen and insulin resistance was observed. Conclusions: Fibrinogen was significantly associated with MS, independent of major confounders. Insulin resistance showed an inconsistent association with fibrinogen.
Aim: High density lipoprotein (HDL) and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B type I (SR-BI). Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by stimulating cholesterol efflux from cells to HDL through ABCA1, ABCG1 and SR-BI. The regulation of ABCA1, ABCG1 and SR-BI expression by cytokines present within the microenvironment of the atheroma may play an important role in determining the impact of reverse cholesterol transport on the atherosclerotic lesion. In the current study, we examined the effect of transforming growth factor-β1 (TGF-β1) on expressions of ABCA1, ABCG1 and SR-BI and explored the role of LXR α in the regulation of ABCA1, ABCG1 and SR-BI in THP-1 macrophage-derived foam cells. Methods and Results: TGF-β1 significantly increased expressions of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by TGF-β1 treatment. Moreover, LXR α was up-regulated by TGF-β1 treatment. In addition, LXR α small interfering RNA completely abolished the promotion effect induced by TGF-β1. Conclusion: These results provide evidence that TGF-β1 up-regulates expressions of ABCA1, ABCG1 and SR-BI through the LXR α pathway in THP-1 macrophage-derived foam cells.
Aim: Cilostazol is a selective inhibitor of phosphodiesterase 3, by which it increases intracellular cAMP and activates protein kinase A, thereby inhibiting platelet aggregation and inducing peripheral vasodilation. We investigated whether cilostazol might prevent nuclear factor (NF)-κB activation by activating AMP-activated protein kinase (AMPK) in vascular smooth muscle cells (VSMC). Methods and Results: Cilostazol was observed to activate AMPK, as well as its downstream target, acetyl-CoA carboxylase, in rat VSMC. Phosphorylation of AMPK with cilostazol was not affected by co-treatment with an adenylate cyclase inhibitor, SQ 22536. Furthermore, a cell-permeable cyclic AMP analog, pCTP-cAMP, did not influence cilostazol-induced AMPK phosphorylation. These findings suggest that cilostazol-induced AMPK activation occurs through a signalling pathway independent of cyclic AMP. Cilostazol dose-dependently inhibited LPS-induced NF-κB activation in the present study. It was also observed to inhibit LPS-induced iNOS gene promoter activity and iNOS gene expression, resulting in markedly reduced NO production. An AMPK inhibitor compound C or siRNA for AMPK attenuated the observed cilostazol-induced inhibition of NF-κB activation by LPS. Ingestion of cilostazol inhibited NF-κB activation, as well as the induction of iNOS mRNA and protein expression, within the aortas of LPS-treated rats. Conclusion: In light of these findings, we suggest that cilostazol might attenuate cytokine-induced expression of the iNOS gene by inhibiting NF-κB following AMPK activation in VSMC.
Aim: To investigate the association between Chlamydia pneumoniae infection and mortality from coronary heart disease, a nested case-control study was conducted for 39,242 Japanese who participated in the JACC Study. Methods: Immunoglobulin A and G titers of C. pneumoniae were measured in stored serum samples collected from 209 patients (113 men and 96 women) who subsequently died of coronary heart disease after 13-year follow-up; and 209 controls matched for gender, age (±5 years) and area of residence. Results: After adjustment for high-sensitive CRP and other cardiovascular risk factors, the multivariate odds ratio (OR) of coronary heart disease for highest vs. lowest tertiles of IgA titers was 2.69 (95%CI, 1.00-7.20), p=0.049 for women and 0.58 (0.23-1.46), p=0.25 for men (p for interaction=0.03). A similar association was observed by high (++) vs. low (-/±) titers of IgA: multivariate OR was 4.09 (0.86-19.4), p=0.07 for women. Conclusions: Since high IgA titers indicate persistent and repeated infection, such a state is associated with an increased risk of coronary heart disease mortality for women.
Aim: To investigate the effect of smoking and smoking cessation on cardio-ankle vascular index (CAVI). Methods: The subjects were 82 smokers (77 men, 64±10 years) and 20 non-smokers (18 men, 61±7 years). CAVI was measured every 3 months and CAVI severity was classified into 3 levels. Decreased, unchanged, and increased CAVI severity levels were coded as “improvement,” “no change,” and “exacerbation,” respectively. Smoking status was coded as “success” for complete abstinence, “partial success” for a reduced number of cigarettes, and “failure” for an unchanging number of cigarettes. Results: Compared with non-smokers, smokers showed a higher CAVI (p<0.05) prior to smoking cessation. Post-cessation, CAVI improved from 9.4 to 8.6 (p<0.01) in “success” cases (n=22), and the significant pre-cessation difference from non-smokers (n=20, CAVI=8.8) disappeared. With regard to the change in CAVI severity of each smoking status, “improvement” occurred in 17%, 24%, and 68% of “failure” (n=35), “partial success” (n=25), and “success” (n=22) groups, respectively, and the “success” group was significantly higher than the other two groups. Conclusion: The study showed that CAVI was increased by smoking, and complete smoking cessation improved CAVI.
Aim: Ultrasound protocols to measure carotid intima media thickness (CIMT) differ considerably with regard to the inclusion of the number of carotid segments and angles used. Detailed information on the completeness of CIMT information is often lacking in published reports, and at most, overall percentages are presented. We therefore decided to study the completeness of CIMT measurements and its relation with vascular risk factors using data from two CIMT intervention studies: one among familial hypercholesterolemia (FH) patients, the Rating Atherosclerotic Disease change by Imaging With A New CETP Inhibitor (RADIANCE 1), and one among mixed dyslipidemia (MD) patients, the Rating Atherosclerotic Disease change by Imaging With A New CETP Inhibitor (RADIANCE 2). Methods: We used baseline ultrasound scans from the RADIANCE 1 (n=872) and RADIANCE 2 (n=752) studies. CIMT images were recorded for 12 artery-wall combinations (near and far walls of the left and right common carotid artery (CCA), bifurcation (BIF) and internal carotid artery (ICA) segments) at 4 set angles, resulting in 48 possible measurements per patient. The presence or absence of CIMT measurements was assessed per artery-wall combination and per angle. The relation between completeness and patient characteristics was evaluated with logistic regression analysis. Results: In 89% of the FH patients, information on CIMT could be obtained on all twelve carotid segments, and in 7.6%, eleven segments had CIMT information (nearly complete 96.6%). For MD patients this was 74.6% and 17.9%, respectively (nearly complete: 92.5%). Increased body mass index and increased waist circumference were significantly (p=0.01) related to less complete data in FH patients. For MD patients, relations were seen with increased waist circumference (p<0.01). Segment-specific data indicated that in FH patients, completeness was less for the near wall of the left (96%) and right internal carotid artery (94%) as compared to other segments (all >98%). In MD patients, completeness was lower for the near wall of both the right and left carotid arteries: 86.0% and 90.8%, respectively, as compared to other segments (all >97%). Conclusions: With the current ultrasound protocols it is possible to obtain a very high level of completeness. Apart from the population studied, body mass index and waist circumference are important in achieving complete CIMT measurements.