Plasma levels of lipoproteins that contain apolipoprotein (apo) CIII predict coronary heart disease (CHD), and associate with contributors to metabolic syndrome such as type 2 diabetes and hypertriglyceridemia. ApoCIII causes hypertriglyceridemia by inhibiting the catabolism and the clearance of TG-rich lipoproteins (TLRs), and the association of apoCIII with CHD has been commonly attributed to these properties; however, it has been untested whether apoCIII itself or in association with lipoproteins directly affects atherogenic mechanisms in vascular cells. This review describes the proatherogenic effect of apoCIII-containing lipoproteins. In brief, apoCIII-rich VLDL (VLDL CIII+) increased the adhesion of human monocytes to vascular endothelial cells (ECs). ApoCIII alone also increased monocyte adhesion to vascular ECs. Interestingly, apoCIII-rich HDL did not reduce the adhesion of monocytes to vascular ECs, whereas HDL without apoCIII decreased their adhesion, suggesting that apoCIII in HDL counteracts the anti-inflammatory property of HDL. ApoCIII alone as well as VLDL CIII+also activated vascular ECs through the activation of NF-κB, and induced the recruitment of monocytes to vascular ECs. Moreover, apoCIII induced insulin resistance in vascular ECs and caused endothelial dysfunction. These findings indicate that apoCIII in TLRs not only modulates their metabolism, but also may directly contribute to the development of atherosclerosis by activating the proinflammatory signal transduction of vascular cells. Here, we propose a novel role for apoCIII that links dyslipidemia with atherosclerosis.
Aim: To characterize lipid profiles conveniently in the fasting period to detect postprandial hyperlipidemic subjects, we measured the concentrations of lipids, including remnant lipoproteins and apoB-48, before and after loading the test meal in 24 normolipidemic subjects. Methods: We examined remnant-like particle-cholesterol and -triglyceride (RLP-C, RLP-TG) by the immune adsorption method, RemL-C by the newly developed homogeneous method, and apoB-48 by chemiluminescence enzyme immunoassay. Results: After loading, TG, RemL-C, RLP-C, RLP-TG, and apoB-48 concentrations were elevated. Twenty subjects had only a slight elevation of TG (low TG group) after loading, while 4 subjects showed apparent increase of TG (more than 150 mg/dL, high TG group). In the fasting period, the high TG group had significantly higher serum concentrations of TG and RemL-C than the low TG group. Although not significant, RLP-C, RLP-TG and apoB-48 concentrations in the high TG group were also higher than in the low TG group. After loading, serum concentrations of TG, RemL-C, RLP-C, RLP-TG, and apoB-48 increased significantly more in the high TG group than in the low TG group. Conclusion: In conclusion, TG, RemL-C, RLP-C, RLP-TG, and apoB-48 concentrations in the fasting period may be suitable for detecting postprandial hyperlipidemic subjects.
Aim: The 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective prescribed drugs for lowering serum cholesterol; however, although statins are extremely safe medications and have brought significant benefits to patients with hypercholesterolemia, they have been shown to produce myalgia, cramps, exercise intolerance and fatigue. The aim of the study was to investigate the molecular mechanisms that may mediate statin myopathy. Methods: We used DNA microarray analysis to examine the changes in gene expression profiles induced by 1 hour and 6 hours of statin treatment on differentiated C2C12 myotubes. Four genes were selected for analysis at the protein level using Western blot analysis on myotubes treated with statin with or without additional mechanical stretching. Results: Eighty-five genes exhibited more than a 2-fold up- or down-regulation in expression, of which 46 have known biological functions related primarily to transmembrane transport, signal transduction, cell growth/maintenance, protein metabolism, or apoptosis. At protein level, three of the four proteins were induced (Adrb1, Socs4 and Cflar) and one was repressed (Birc4). Changes in protein expression largely mirrored the changes in their corresponding transcripts, although the fold-change was less dramatic. The addition of imposed muscle fiber stretching did not exacerbate the expression of these genes at the protein level with the exception of Cflar, a pro-apoptotic protein. Conclusion: These data suggested that alterations in the expressions of some statin-regulated genes could be causative factors for statin toxicity in muscle. Repression of the anti-apoptosis gene (Birc4) and activation of the pro-apoptosis gene (Cflar) indicated that cell death may play an important role in statin-induced myopathy.
Aims: The clinical implications of stiffness of the carotid artery (CA) have not been fully clarified in the prediction of coronary artery disease (CAD), although intima-media thickness (IMT) has been established as a surrogate marker. We examined the associations of stiffness parameter β (ST) and IMT with concurrent CAD. Methods: IMT and ST were measured by ultrasound in 439 nondiabetic subjects as a control and 1528 type 2 diabetic subjects (T2DM) with or without CAD in a cross-sectional study. Results: Both IMT and ST significantly increased with age and group category, in the order of control, T2DM without CAD, and T2DM with CAD (p<0.001). The area under the curve on ROC analysis of ST for concurrent CAD was comparable to that for IMT. On multivariate logistic regression analysis, High IMT (≥1.30 mm) and High stiffness (≥20.0) had significant odds ratios for concurrent CAD (2.205, p<0.001 and 1.548, p<0.05, respectively). The group with High IMT and High Stiffness exhibited a stronger multivariate odds ratio (3.115, p=0.0001). Conclusions: ST and IMT are associated with CAD and exhibited significant odds ratios for CAD. Our findings suggest that the combination of IMT and ST is a useful marker of atherosclerosis.
Aim: Little is known about the prognostic value of q wave abnormality for cardiovascular disease (CVD) on a resting electrocardiogram (ECG) of the Japanese general population with an extremely low incidence of myocardial infarction. Methods: We followed 8,339 participants without a past and present history of CVD for 19 years. The multivariate-adjusted hazard ratio (HR) of q wave abnormality for CVD mortality was estimated by the Cox proportional hazards model. Results: The multivariate-adjusted HR of composite findings of moderate or severe q wave abnormality was 1.75 (95% confidence interval (CI): 0.973.17) for mortality due to CVD and 2.97 (95%CI: 1.436.16) due to heart diseases. The multivariate-adjusted HR of mild abnormality for mortality from heart diseases was 1.95 (95%CI: 1.003.81). The relationship between moderate or severe abnormalities and mortality from CVD was unchanged when participants with ST-T changes and high amplitude R waves were excluded and when participants were divided by the presence of major CVD risk factors such as hypertension. Q wave abnormality was not associated with the risk of stroke. Conclusion: Moderate or severe q wave abnormalities are prominent and important predictors of mortality due to CVD and heart disease in the Japanese general population without CVD history.
Aim: Information about the effects of HMG-CoA reductase inhibitor (statin) treatment on lipoprotein subclasses has been severely limited. Nuclear magnetic resonance (NMR) spectrometry has emerged as a new methodology to quantify lipoprotein subclass concentrations. In the present study, we attempted to evaluate the hypolipidemic effects of atorvastatin utilizing this method. Methods: Twenty-six patients were administered with atorvastain 10 mg daily for 4 weeks. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy. Inflammation markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1), were also determined. Results: Additional to a marked reduction of LDL-C (-43%), atorvastatin treatment significantly decreased TG, RLP-C, apoC-II, apoC-III, and apoE by 27%, 49%, 25%, 15%, and 28%, respectively. NMR analysis revealed marked reductions of all LDL subclasses, resulting in a significant reduction of LDL particle number as well as an increase in LDL particle size. Further, some VLDL were decreased and HDL particle size was increased by atorvastatin. Among inflammation markers, MDA-LDL and IL-6 were marginally to significantly decreased. Conclusion: In addition to a strong LDL-C lowering function, atorvastatin exerts beneficial effects on TG-rich lipoproteins and inflammation in hypercholesterolemic patients.
Background: Patients with chronic kidney disease (CKD) have a high prevalence of cardiovascular disease (CVD). Arterial stiffness plays an important role in the pathogenesis of CVD; however, to date, there have been no reports of the assessment of arterial stiffness in patients at different stages of non-diabetic CKD. Methods: We studied 50 patients with non-diabetic CKD (stages 15, 5D) receiving medical treatment at Tokyo Women's Medical University. Pulse wave velocity (PWV) was assessed using an applanation tonometer to determine arterial compliance. All current medications were recorded and biochemical parameters were analyzed. Results: Non-diabetic CKD stage 5D patients had a higher PWV, and higher serum levels of C-reactive protein (CRP), Ca, P and intact parathyroid hormone (iPTH) than non-diabetic CKD stage 15 patients (p=0.03, p=0.009, p=0.006, p=0.00005, and p=0.002, respectably). As compared to non-diabetic CKD stage 12 patients, patients with non-diabetic CKD stage 35 were older, and had higher serum levels of P and iPTH and a higher PWV (p=0.0002, p=0.009, p=0.03, and p=0.004). Nephrosclerosis was associated with a higher PWV, higher serum levels of CRP, and a higher prevalence of CVD than patients with CKD of other origins. Conclusion: We showed a stepwise increase of arterial stiffness with increasing disease severity stage in patients with CKD not associated with diabetes mellitus. CKD caused by nephrosclerosis was found to be associated with increased arterial stiffness and to be a risk factor for CVD.