Mammalian somatic cells do not catabolize cholesterol and therefore export it for sterol homeostasis at cell and whole body levels. This mechanism may reduce intracellularly accumulated excess cholesterol, and thereby would contribute to the prevention or cure of the initial stage of atherosclerotic vascular lesion. High-density lipoprotein (HDL) plays a central role in this reaction by removing cholesterol from cells and transporting it to the liver, the major cholesterol catabolic site. Two independent mechanisms have been identified for cellular cholesterol release. The first is non-specific diffusion-mediated cholesterol “efflux” from the cell surface, in which cholesterol is trapped by various extracellular acceptors including lipoproteins. Extracellular cholesterol esterification of HDL provides a driving force for the net removal of cell cholesterol by this pathway, and some cellular factors may enhance this reaction. The other mechanism is an apolipoprotein-mediated process to generate new HDL particles by removing cellular phospholipid and cholesterol. This reaction is mediated by a membrane protein ATP-binding cassette transporter A1 (ABCA1), and lipid-free or lipid-poor helical apolipoproteins recruit cellular phospholipid and cholesterol to assemble HDL particles. The reaction is composed of two elements: the assembly of HDL particles with phospholipid by apolipoprotein, and cholesterol enrichment in HDL. ABCA1 is essential for the former step and the latter requires further intracellular events. ABCA1 is a rate-limiting factor of HDL assembly and is regulated by transcriptional and post-transcriptional factors. Post-transcriptional regulation of ABCA1 involves modulation of its calpain-mediated degradation.
There has been a significant increase in the prevalence of type 2 diabetes mellitus (T2DM) in Vietnam. We found that Vietnamese with T2DM had a normal body mass index (BMI), but high levels of total body fat and abdominal fat. Based on published reports together with our own findings, we believe that a sedentary lifestyle and an abundance of starchy foods and also Western style energy-rich foods are factors associated with disease. The staple food of the Vietnamese is still polished-rice which has high glycemic index values. In addition, a Westernized diet, and the chronic consumption of high-glycemic index foods together with a sedentary lifestyle result in insulin resistance and diabetes. The average BMI of T2DM patients is ≤ 23 kg/m2, greater than that 20 years ago. In addition,these patients have high levels of body fat, especially abdominal fat, measured as the waist to hip ratio (WHR ≥ 0.90). We therefore, tentatively suggest a BMI of 23 kg/m2 together with a WHR of 0.90 for males and 0.85 for females as new cutoff values for the risk of T2DM in Vietnamese. These findings have important implications for primary prevention because they indicate that screening and intervention should focus on high-risk populations.
This review summarizes both the structure and function of IL-1 receptor antagonist (IL-1Ra), and relates our new findings, particularly those obtained in IL-1Ra-deficient mice (IL-1Ra-/-), to the role of IL-1Ra in arterial diseases and cholesterol metabolism. IL-1Ra-/- mice show an increase in neointima-formation after arterial injury. Heterozygosity in the IL-1Ra gene against the apolipoprotein E-deficient background revealed a role for IL-1 in promoting atherogenic cell signaling and that the larger lesions of IL-1Ra-/- mice are enriched in macrophages and depleted of smooth muscle cells. Furthermore, IL-1Ra-/- mice developed severe fatty livers and hypercholesteroremia following 20 weeks on a atherogenic diet compared to WT mice. Taken together, these results suggest that IL-1Ra plays important roles in restenosis after angioplasty, the development of atherosclerosis, and the metabolism of cholesterol in vivo.
Calcification is a common finding in human coronary arteries. However, there is conflicting evidence for a link between calcification and plaque instability. Current intravascular ultrasound (IVUS) technology allows a definitive detection of the calcification and measurement of the vessel wall. Using preinterventional IVUS images, we clarified that in patients with acute myocardial infarction, small “spotty” calcifications prevailed, associated with a fibrofatty plaque and positive remodeling. Conversely, in patients with stable angina pectoris, extensive calcification was frequent. IVUS allows the detection of vulnerable plaques in coronary arteries, by identifying not only a large lipid core and positive remodeling, but also a spotty pattern of calcification.
Recent findings suggest that the oxidative modification of low-density lipoproteins (LDL) and an increase in triglyceride-rich lipoprotein particles including chylomicron remnants contribute to the progression of atherosclerosis, as does the inflammatory response. We therefore examined whether and how these lipoproteins affected interleukin (IL)-1β release and mRNA expression for IL-1β and IL-18 in THP-1 cells, a human monocyte cell line. Chylomicron remnants increased IL-1β release into the conditioned medium by THP-1 in a dose- and time-dependent manner. At concentrations up to 1 μg/ml, chylomicron remnants increased IL-1β release by 4-fold compared with the control. Neither native LDL nor oxidized LDL (OxLDL) significantly increased IL-1β release. Chylomicron remnants increased IL-1β mRNA expression by 3 times. Native LDL or OxLDL did not increase IL-1β mRNA, while neither these lipoproteins nor chylomicron remnants increased IL-18 mRNA. Chylomicron remnants also increased the activities of caspase-1 and nuclear factor (NF)-κB significantly, while native LDL or OxLDL did not. In conclusion, chylomicron remnants stimulated IL-1β mRNA expression and IL-1β protein production probably via caspase-1 and NF-κB activation in THP-1 cells.
Metabolic syndrome, indicated by insulin resistance/hyperinsulinemia, obesity, central obesity, atherogenic dyslipidemia, and hypertension, contributes to atherosclerotic cardiovascular disease. However, it is controversial whether the indicators of metabolic syndrome are related to subclinical atherosclerosis collectively or individually. Whether there is any gender-based difference in the mechanisms of metabolic syndrome-induced atherosclerosis progression is also unknown. Two models were compared in this study. Model 1 assumes that a latent factor, metabolic syndrome per se, impacts subclinical atherosclerosis (collective effects model); Model 2 assumes the effect of the syndrome is mediated through its indicators (individual effects model). Data were obtained from the Los Angeles Atherosclerosis Study. The cohort consists of 573 adults (age, 40−60 years) who were asymptomatic for cardiovascular disease. Subclinical atherosclerosis was assessed by measuring common carotid artery intima-media thickness (CCA-IMT) using B-mode ultrasound. Three examinations were completed at 1.5-year intervals from 1995−1999. The analyses were performed with SAS 8.2 and AMOS 4.0. The results showed that atherogenic effects of metabolic syndrome were mediated through its indicators; there were gender-based differences in the mechanisms of metabolic syndrome-induced atherosclerosis. Central obesity was significantly associated with the baseline IMT for men only, whereas triglycerides were significantly associated with the progression of IMT for women only. Systolic blood pressure was significantly associated with the baseline and progression for both men and women. However, fasting insulin was not found to be significantly associated with the baseline and progression of IMT in the multivariate model, although it was significantly associated with other components of metabolic syndrome.
We analyzed lipoprotein profiles in 616 Japanese by biphasic agarose gel electrophoresis using Chol/Trig ComboTM to yield HDL, VLDL, LDL and CM fractions which were stained with cholesterol and triglyceride reagents, respectively. To further evalute the pattern of electrophoresis, we analyzed the fraction between VLDL and LDL to confirm the possibility of a MidBand by using an automatic-five-fraction function. The cholesterol concentrations in MidBand (MidBand-C) showed a good correlation to remnant-like particle-cholesterol (RLP-C) (r = 0.95) in 23 consecutive samples (TC < 220 mg/dl, Lp(a) < 30 mg/dl). However, MidBand-C concentrations of subjects with high Lp(a) levels (Lp(a) > 30 mg/dl) were also high compared to RLP-C concentrations. The average MidBand-C levels in elderly normolipidemic control subjects (TC < 220, TG < 150) were 5.2 ± 2.4 mg/dl in 30 males (mean age, 70 ± 10 years) and 5.4 ± 2.0 mg/dl in 40 females (64 ± 11 years). The average MidBand-C levels of normolipidemic patients with coronary artery diseases (CAD; TC < 220, TG < 150) were 9.4 ± 4.1 mg/dl in 126 males (mean age, 66 ± 10 years) and 9.1 ± 4.0 mg/dl in 44 females (67 ± 10 years). These levels were significantly higher than control values (p < 0.0001). Areas under ROC curves were greater for MidBand-C than for TC, LDL-C and TG when used to discriminate between the patients with CAD and normolipidemic control subjects for each sex. There results suggest that the MidBand-C level may be useful as an indicator of risk for CAD.
To investigate risk factors for coronary artery disease (CAD), we analyzed the clinical parameters of patients with a coronary artery bypass graft (CABG) in a case-control study. Eighty-eight patients (75 males and 13 females) who underwent CABG surgery between 2001 and 2002 were compared with age- and sex-matched healthy controls randomly chosen from the registry of Kobari Health Care Center. Wilcoxon’s signed rank test and McNemar’s test were used for pairwise comparisons. Multivariate logistic regression analysis was used to identify significant risk factors for CABG. Significant differences between the patients and controls were observed in HDL-C (p < 0.001), HbA1c (p < 0.001), Brinkman Index (BI; p < 0.001), body mass index (BMI; p = 0.002), and systolic blood pressure (SBP; p = 0.013). Subjects with an abnormal BMI, HbA1c, or HDL-C or high BI value made up a significantly higher proportion of the patients who underwent CABG, compared to their age- and sex-matched controls. Multivariate logistic regression analysis identified high levels of HbA1c, low levels of HDL-C, and high scores on the BI as significant risk factors for needing a CABG. These results demonstrate that, despite the modification of laboratory determinations by antecedent treatment, HDL-C, HbA1c, BI, BMI, and SBP are significant indicators of risk for CAD.
To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2’deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total- and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 ± 7.5 to 8.1 ± 4.2 ng/mg/Cr in the atorvastatin group (p < 0.05) and 12.3 ± 8.8 to 6.8 ± 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 ± 4.9 to 9.2 ± 3.4 ng/mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 ± 8.2 to 6.67 ± 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress.