Dysregulation of adipose tissue-derived bioactive molecules, termed adipokines, is recognized as common ground for insulin resistance and metabolic syndrome associated with obesity. However, adipokine dysregulation is paradoxically associated with lipodystrophy and lipoatrophy with aging. In familial partial lipodystrophic syndromes and Hutchinson-Gilford progeria syndrome, both of which are caused by mutations in the LMNA gene, loss of adipose tissue is associated with adipokine dysregulation, insulin resistance, and atherosclerosis, suggesting a critical role of adipose tissue function in controlling whole body energy metabolism, age-related pathologies, and longevity. Centenarians, a model of healthy aging and longevity, are reported to exhibit preserved insulin sensitivity as well as favorable adipokine profiles, particularly high levels of circulating adiponectin. Furthermore, adipose tissue dysfunction indicated by dysregulation of leptin, tumor necrosis factor-α, and adiponectin is associated with poor prognosis in centenarians. In contrast to results obtained for obesity, adipokine dysregulation in centenarians is associated with very low leptin levels, suggesting that age-related lipoatrophy is the major factor for adipose tissue dysfunction at an advanced age. These observations suggest that adipose tissue excess as well as its aging is implicated in the regulation of adipokines, insulin sensitivity, and lifespan in humans.
Vascular calcification has been associated with the incidence of cardiovascular events and thus there has been interest in better understanding its pathogenesis. Early theories considered vascular calcification to be a passive process which occurred as a non-specific response to tissue injury or necrosis. More recent theories propose vascular calcification results from loss of molecular inhibitors or via an active cell mediated process. The origin of the cells responsible for vascular calcification is controversial and may vary in different sites and patients. Calcification has been reported as result of apoptosis or death of vascular smooth muscle cells for example. One novel source of cells controlling vascular calcification is from the bone marrow. A circulating immature bone marrow derived population has been identified and a small subset of this bone marrow population has been reported to possess bone forming properties in vitro and hence termed osteo-progenitors. This article reviews evidence supporting the contribution of these naive bone marrow derived circulating osteo-progenitor cells in vascular calcification.
Aim: Platelets play a pivotal role in atherothrombotic diseases. Platelet aggregability induced by agonists has great interindividual variability; however, the factors influencing platelet aggregability variation have not been characterized in Asia. Methods: To examine the confounding factors influencing platelet counts and responsiveness to agonists, we measured the platelet counts and platelet aggregability induced by 1.7 µM adenosine diphosphate (ADP) or 1.7 µg/mL collagen using a light transmittance aggregometer in the Japanese general population without medication or cardiovascular disease (387 men and 550 women) in the Suita Study. Results: Platelet counts were negatively correlated with age in both men and women (Spearman's rank correlation coefficient: rs=−0.230 and −0.227; p< 0.01, respectively). In women, platelet counts were correlated negatively with the high-density lipoprotein (HDL) cholesterol level and positively with the low-density lipoprotein (LDL) cholesterol/HDL cholesterol (L/H) ratio (rs=−0.135 and 0.119; p< 0.01, respectively). In women, platelet aggregabilities by ADP and collagen were correlated with age (rs=0.118 and 0.143; p< 0.01, respectively), and collagen-induced platelet aggregability was correlated with the LDL cholesterol level, the L/H ratio, and the non-HDL cholesterol level (rs=0.167, 0.172, and 0.185; p< 0.01, respectively). Even after adjustment for age, systolic blood pressure, body mass index, and current smoking and drinking, the association of platelet counts with the L/H ratio in women and associations of collagen-induced platelet aggregability with the L/H ratio and the non-HDL cholesterol level remained. Conclusion: Examination of platelet counts and platelet aggregability induced by ADP and collagen revealed gender, age and lipid levels as factors influencing inter-individual variability.
Aim: Oxidised low-density lipoprotein (LDL) is considered a risk marker for cardiovascular disease. However, it remains unclear whether oxidised LDL concentrations differ with the physical activity status in older adults. The purpose of this study was to examine the relationship between the amount of physical activity and oxidised LDL in older adults. Methods: Twenty-seven older adults (aged 69.9±4.3 years, mean±SD.; 16 female and 11 male) were analysed in the cross-sectional design. Prior to blood collection, participants were asked to wear an uniaxial accelerometer for 4 consecutive weeks to determine the physical activity status. After a 48-h period of physical activity avoidance and a 10-h overnight fast, fasting venous blood samples were obtained from each participant. Results: Fasting plasma oxidised LDL concentrations and plasma monocyte chemoattractant pro-tein-1 concentrations were negatively correlated with the amount of physical activity (r=−0.409, p=0.034; r=−0.385, p=0.047, respectively). Conclusions: This study demonstrates that regular physical activity may play a protective role in the oxidation of LDL in older adults.
Aim: In-stent restenosis (ISR) remains the major limitation of percutaneous coronary intervention (PCI), and the mechanism of ISR is neointimal growth. Higher serum total bilirubin (TBIL) inhibits the inflammatory response and the proliferation of vascular smooth muscle cells; however, the relationship between TBIL and ISR is still unclear. This study aimed to determine whether the serum bilirubin level is associated with ISR after coronary stenting in patients with coronary artery disease. Methods: This study investigated 1076 consecutive patients who underwent coronary stenting and follow-up angiography (average period: 236 days) using the Fukuoka University Hospital Registry. We used multivariate logistic regression analysis to identify independent predictors of ISR. Results: The baseline TBIL level was significantly lower in patients with ISR at follow-up compared to those without ISR [0.53±0.26 mg/dL vs. 0.62±0.69 mg/dL, p= 0.036]. When we divided the patients into 4 groups according to their baseline TBIL level [“low”, “low-normal”, “high-normal group” and “high” (0.18±0.04, 0.50±0.13, 0.93±0.12 and 2.11±2.68 mg/dL)], the ISR rate at follow-up was significantly correlated with the TBIL level [31.0, 32.3, 22.1, and 15.6%, respectively; p= 0.008 for trend]. A significant negative correlation between the TBIL level and ISR was revealed by multivariate analyses [odds ratio, 0.6; 95% confidence interval, 0.39-0.89, p= 0.015]. This risk reduction was comparable to those of other known ISR risk factors and covariates. Conclusion: To the best of our knowledge, this is the first report to demonstrate that a higher TBIL level may be a useful independent predictor of ISR risk after PCI.
Aim: Evidence of relationships between lipid peroxidation and the incidence of coronary heart disease is limited. We therefore investigated this association in a Japanese general population. Methods: We prospectively studied 1945 individuals who were apparently healthy at the baseline. Cox proportional-hazards models were used to investigate the relationship between serum levels of thiobarbituric acid-reactive substances (TBARS) as a marker of lipid peroxidation and the incidence of coronary heart disease, adjusted for established risk factors including age, sex, current smoking, body mass index, systolic blood pressure, glycohemoglobin A1c, serum total cholesterol, and serum high-density lipoprotein cholesterol levels. Results: During 20,226 person-years of follow-up (median follow-up, 10.9 years), 44 coronary events were documented. The risk of coronary heart disease increased in consecutive tertiles of the TBARS level. On age-and sex-adjusted analysis, the level of TBARS was significantly associated with the incidence of coronary heart disease. The hazard ratio in the highest tertile compared with the lowest tertile was 3.22 (95% confidence interval, 1.38 to 7.53; p= 0.007). On multivariate analysis adjusted for age, sex, and other established risk factors, this association remained significant (hazard ratio, 3.23; 95% confidence interval, 1.28 to 8.16; p= 0.01). Conclusions: Serum levels of TBARS are a strong and independent predictor of coronary heart disease. These findings support the hypothesis that lipid peroxidation is an important risk factor for coronary heart disease.
Aim: Most studies have reported that circulating levels of adiponectin are negatively correlated with the body mass index (BMI), and hypoadiponectinemia is related to cardiometabolic disorders; however, not all obese subjects have hypoadiponectinemia. The present study investigated circulating adiponectin levels and fat distribution, i.e. subcutaneous fat area (SFA) and visceral fat area (VFA), in obese subjects. Methods: Sixty-eight obese Korean subjects underwent fat distribution by computed tomography (CT) scan and laboratory tests including circulating total adiponectin levels (APN) and circulating high molecular weight adiponectin levels (HMW-APN). Results: Log-APN and log-HMW-APN did not correlate with log-BMI either in obese males or females in this study; however, log-APN significantly and negatively correlated with log-VFA both in obese males (r=−0.691, p=0.009) and females (r=−0.319, p=0.002), and log-HMW-APN also correlated negatively with log-VFA both in obese males (r=−0.650, p=0.016) and females (r=−0.370, p=0.005). Log-VFA was a significant determinant of log-APN and log-HMW-APN in obese subjects. In contrast, neither log-APN nor log-HMW-APN was significantly correlated with log-SFA in obese males and females. Conclusions: The present study demonstrated that APN and HMW-APN correlated with VFA, but not BMI and SFA, in obese subjects, and suggest that hypoadiponectinemia may represent dysfunction of adipose tissue in obesity.
Aim: Oxidized low-density lipoprotein (oxLDL) interacts with macrophages and is implicated in atherogenesis. Macrophages are also the major source within the atherosclerotic plaque of tissue factor (TF), the membrane-bound glycoprotein receptor that triggers the coagulation cascade in vivo and contributes to plaque thrombogenicity. In this study we tested the hypothesis that oxLDL modulates TF expression in human monocyte-derived macrophages (MDMs). Methods: Mononuclear cells were isolated from human blood, allowed to differentiate into MDMs during 8 days in cell culture, and then exposed to varying concentrations of oxLDL in the presence or absence of lipopolysaccharide (LPS). TF procoagulant activity (TF-PCA) of MDMs was measured by one-stage recalcification clotting assay using human recombinant TF as standard. TF protein was evaluated by Western blotting, and TF mRNA was determined by Northern blot analysis. Results: OxLDL at 5-10 µg/mL increased TF-PCA, TF protein, and mRNA in MDMs, whereas 20-100 µg/mL oxLDL inhibited TF-PCA, protein expression, and mRNA expression in these cells even in the face of LPS stimulation. Conclusions: Low concentrations of oxLDL enhance TF expression in MDMs, whereas higher concentrations attenuate TF expression both at baseline as well as following LPS stimulation. Both TF-PCA and TF protein follow this dose-response pattern that is preceded by concordant mRNA changes. Thus, we have demonstrated modulation by oxLDL of TF protein and bioactivity in MDMs.
Aims: The cellular and molecular mechanisms and safety after drug-eluting stent (DES) implantation in diabetic patients are still poorly understood; therefore, in this study, we evaluated the pathologic responses of the sirolimus-eluting stent (SES) or paclitaxel-eluting stent (PES) in a type I diabetes mellitus (DM) rat model. Methods: The type I DM rat model was manipulated by intra-peritoneal streptozotocin injection. Two weeks later, DES was implanted in the aorta of rats with hyperglycemia or not as a control. Four weeks after DES implantation, the stented aorta was isolated and histomorphometric analysis was performed. Results: On histomorphometric analysis, increased thrombus, inflammatory cell infiltration, and neointimal hyperplasia (NIH) without change of the smooth muscle cell number after DES implantation were observed in DM rats compared with non-DM (NDM) rats. Furthermore, delayed coverage of mature endothelial cells defined as a von Willebrand factor expression and increased immature endothelial cells as a c-kit expression after DES implantation were observed in DM rats compared with NDM rats. Increased fibrin deposition and decreased hyaluronic acid accumulation at NIH after DES implantation were also observed in DM rats compared with NDM rats. Conclusions: In conclusion, the main mechanism of restenosis after DES implantation under hyperglycemic conditions was initial thrombus with changes of the extracellular matrix rather than SMC proliferation. These results provided a therapeutic clue for the selection of DES and application of combination therapy using anti-thrombotic and anti-inflammatory drugs in diabetic patients.
Aim: Multimer complex formation of adiponectin is recognized as an important mechanism modulating the biological functions of this adipokine, but the role of adiponectin isoforms in myocardial infarction (MI) is still unclear. Methods: We quantified total adiponectin (TOTAL), high, middle, and low molecular weight adiponectin multimers (HMW, MMW, LMW) in a study of non-diabetic obese (BMI ≥ 30 kg/m2) and normal-weight (BMI ≤ 25 kg/m2) male subjects with MI and healthy controls (n=180). Subsequently, we designed a prospective nested-case-control study to investigate the association of the adiponectin multimers with fatal and non-fatal MI in n=1236 initially healthy non-diabetic men. Results: Obesity was significantly related to lower levels of TOTAL, HMW, MMW, and LMW in subjects with and without MI (p < 0.01, each). In contrast, MI was strongly related to MMW/TOTAL (p < 0.0001), inversely to HMW/TOTAL (p < 0.0001), but not TOTAL or LMW levels. In particular, the median MMW/HMW ratios were markedly different in men with MI (1.71, interquartile range (1.08-2.40)) and without (0.72 (0.49-1.08), p < 0.0001). In the prospective study, 56 incident fatal and non-fatal MI events occured. The MMW/HMW ratio was associated with fatal and non-fatal MI up to 5 years before the event. The β-estimates for the relationship between MMW/HMW and incident MI decreased with increasing time to the event. Conclusions: Whereas total adiponectin and all isoforms are related to obesity, total adiponectin and LMW levels are not associated with MI in non-diabetic men. In contrast, the MMW/HMW-ratio correlated with incident MI up to 5 years before the event. These data imply that measurement of adiponectin multimers adds significant value in assessing cardiovascular risk compared to total adiponectin alone.