Both type I and type V hyperlipoproteinemia are characterized by severe hypertriglyceridemia due to an increase in chylomicrons. Type I hyperlipoproteinemia is caused by a decisive abnormality of the lipoprotein lipase (LPL)- apolipoprotein C-II system, whereas the cause of type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. Since the relationship of hypertriglyceridemia with atherosclerosis is not as clear as that of hypercholesterolemia, and since type I and V hyperlipoproteinemia are relatively rare, few guidelines for their diagnosis and treatment have been established; however, type I and V hyperlipoproteinemia are clinically important as underlying disorders of acute pancreatitis, and appropriate management is necessary to prevent or treat such complications. Against such a background, here we propose guidelines primarily concerning the diagnosis and management of type I and V hyperlipoproteinemia in Japanese.

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Aim: The receptor for advanced glycation end-products (RAGE) has been suggested to play a pivotal role in the development of diabetic vasculopathy and atherosclerosis; however, due to its low expression, the physiological role of RAGE in vascular smooth muscle cells (VSMC) remains unknown.
Methods: Using VSMC lines stably expressing RAGE (RAGE-A10), we studied the molecular mechanism by which S100B, a RAGE ligand, induces proinflammatory gene expression.
Results: S100B induced NF-κB activation and the expression of several proinflammatory genes (MCP-1, IL-6, ICAM-1) at mRNA and protein levels in RAGE-A10, among which MCP-1 expression was the most robust. S100B-induced MCP-1 expression was dose-dependently blocked by inhibitors of JNK (SP600125), p38 (SB203580), MEK-1 (U0126) as well as NF-κB (Bay117085). In RAGE-A10, S100B activated JNK, MEK-1 and p38. S100B-induced MCP-1 promoter activity via NF-κB binding sites and nuclear translocation of NF-κB p65 subunit were blocked by SP600125, U0126, and SB203580 in RAGE-A10.
Conclusion: Our study demonstrates that S100B increased MCP-1 expression via NF-κB and mitogen-activated protein kinase (JNK, ERK1/2, and p38) pathways in RAGE-overexpressed A10 cell lines. Thus, RAGE-A10 could be a useful cell model for studying the molecular mechanism(s) of up-regulated RAGE in the vasculature.

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Aim: Connective tissue growth factor (CTGF), a direct target gene of transforming growth factor-β (TGF-β) signaling, plays an important role in the development of atherosclerosis. We previously showed that Runx2, a key transcription factor in osteoblast differentiation, regulates osteogenic conversion and dedifferentiation of vascular smooth muscle cells (VSMCs). In this study, we investigated the hypothesis that Runx2 modulates CTGF gene expression via the regulation of TGF-β signaling.
Methods and Results: Expression of the Runx2 gene was decreased, and CTGF mRNA levels were reciprocally increased by TGF-β in a time-dependent manner in cultured human aortic smooth muscle cells (HASMCs) and C3H10T1/2 cells. Forced expression of Runx2 decreased and the reduction of Runx2 expression by small interfering RNA enhanced both basal and TGF-β-stimulated CTGF gene expression in HASMCs. Site-directed mutation analysis of the CTGF promoter indicated that transcriptional repression by Runx2 was mediated by the Smad-binding element (SBE) under basal and TGF-β-stimulated conditions. Data obtained from immunoblots of Runx2-, Smad3- or Smad4-transfected cells and chromatin immunoprecipitation analysis indicated that Runx2 interacts with Smad3 at the SBE. Immunohistochemistry revealed that the expression of Runx2 and CTGF was distinct and almost mutually exclusive in human atherosclerotic plaque.
Conclusions: These results for the first time demonstrate that Runx2/Smad3 complex negatively regulates endogenous and TGF-β-induced CTGF gene expression in VSMCs. Thus, the induction of Runx2 expression contributes to the phenotypic modulation of VSMCs, in which the TGF-β/Smad pathway plays a major role.

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Aim: Tumor necrosis factor receptor 1 (TNFR1) participates importantly in arterial inflammation in genetically altered mice; however it remains undetermined whether a selective TNFR1 antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist in the suppression of arterial inflammation.
Methods: We investigated intimal hyperplasia in IL-1 receptor antagonist-deficient mice two weeks after inducing femoral artery injury in an external vascular cuff model. All mice received intraperitoneal injections of TNFR1 antagonist (PEG-R1antTNF) or normal saline twice daily for 14 days.
Results: PEG-R1antTNF treatment yielded no adverse systemic effects, and we observed no significant differences in serum cholesterol or blood pressure in either group; however, selective PEG-R1antTNF treatment significantly reduced intimal hyperplasia (19,671±4,274 vs. 11,440±3,292 µm²; p=0.001) and the intima/media ratio (1.86±0.43 vs. 1.34±0.36; p=0.029), compared with saline injection. Immunostaining revealed that PEG-R1antTNF inhibits Nuclear factor-κB (NF-κB), suppressing smooth muscle cell (SMC) proliferation and decreasing chemokine and adhesion molecule expression, and thus decreasing intimal hyperplasia and inflammation.
Conclusions: Our data suggest that PEG-R1antTNF suppresses SMC proliferation and inflammation by inhibiting NF-κB. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.

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Aim: While smoking cessation (SC) leads to a reduction of cardiovascular events, atherogenic biomarkers specifically connected with cigarette smoking and SC are unknown. Circulating levels of oxidatively modified low-density-lipoprotein (LDL) are associated with a high risk of cardiovascular diseases. Recently, two novel, oxidatively modified LDL markers, serum amyloid A-LDL (SAA-LDL) and α1-antitrypsin-LDL (AT-LDL), were identified; however, the significance of SAA-LDL and AT-LDL as cardiovascular risk markers is unknown.
Methods: We carried out a cross-sectional study involving 243 patients, and determined serum levels of SAA-LDL and AT-LDL.
Results: Both serum levels of SAA-LDL and AT-LDL were significantly increased in current compared to non-current smokers. Stepwise regression analysis revealed that the current smoking status and duration of smoking were strong independent determinants of the AT-LDL level. In contrast, high-sensitivity C-reactive protein was the strongest determinant of the SAA-LDL level. In multiple logistic regression analysis, the current smoking status was most closely associated with the AT-LDL level. Successful SC employing a 12-week program significantly increased the body mass index and serum levels of obesity-related markers. Notably, successful SC significantly decreased levels of AT-LDL, but not those of SAA-LDL.
Conclusions: The present study provides the first evidence for the distinct characteristics of two novel, oxidatively modified LDL markers, SAA-LDL and AT-LDL. In contrast to SAA-LDL, an inflammatory marker, AT-LDL serves as a marker of smoking-specific oxidative stress. These findings warrant further investigations to clarify if AT-LDL provides a key link between smoking and cardiovascular diseases.

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Aim: Adipokines have been implicated in the pathogenesis of obesity and obesity-related disorders, including atherosclerosis. Chemerin is a recently discovered adipokine which is closely correlated with various metabolic phenotypes in humans. We examined the association between circulating chemerin levels and arterial stiffness, as represented by the brachial ankle pulse wave velocity (baPWV).
Methods: Fifty-eight obese and 62 non-obese individuals participated in the study. We measured the serum chemerin and high sensitivity C-reactive protein (hsCRP) levels, and the homeostasis model assessment of insulin resistance (HOMA-IR), as well as other cardiovascular risk factors. Vascular health was assessed by the baPWV and carotid intima-media thickness (IMT).
Results: The serum chemerin level was significantly increased in obese individuals compared with lean controls (120.14±19.43 ng/mL vs. 106.81±23.39 ng/mL, p = 0.001). The circulating chemerin level had a significant positive correlation with the body mass index, waist circumference, HOMA-IR, and low-density lipoprotein-cholesterol, triglycerides, and hsCRP levels. The serum chemerin level was significantly associated with the baPWV (r= 0.280, p= 0.002), but not the carotid IMT (r= 0.065, p= 0.504). Multiple stepwise regression analysis showed that age (p < 0.001), waist circumference (p= 0.038), systolic blood pressure (p < 0.001), and serum fasting glucose (p= 0.003) and chemerin levels (p= 0.017) were definitive risk factors for arterial stiffness (r²=0.457).
Conclusions: The circulating chemerin level was an independent risk factor for arterial stiffness even after adjusting for other cardiovascular risk factors.

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Aim: To investigate the prevalence and geographical variation of high arterial stiffness in groups from the Amami islands (Amami) and Kagoshima mainland (mainland), Japan, using the cardio-ankle vascular index (CAVI) as a surrogate marker of arterial stiffness.
Methods: We recruited 4,523 health checkup examinees from Amami and 440 examinees from the mainland, with an age range of 40-69 years. The frequency of high arterial stiffness (CAVI≥9.0) was geographically compared between the regions, and both mean CAVI values were compared with those of the healthy Japanese population with less risk factors for coronary artery disease. Clinical, lifestyle, and regional factors for increased CAVI values were estimated by the multiple linear regression model.
Results: The frequency of high arterial stiffness on Amami was significantly lower than on the mainland. Mean CAVI values on Amami were similar in males and lower in females than in the healthy Japanese population, but those on the mainland were higher for both sexes. Age, systolic blood pressure, triglycerides, fasting blood glucose, and a history of hypertension and diabetes mellitus were positively related to increased CAVI values on Amami. The regional factor of Amami, compared with the mainland, was negatively related to increased CAVI values in both sexes after adjusting for traditional cardiovascular risk factors.
Conclusion: CAVI values in Amami residents were significantly lower than in mainland residents, suggesting that environmental or genetic factors might have improved arterial stiffness in the Amami population.

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Aim: To investigate the possible mechanisms and association of increased complexes of β₂-glycoprotein I with lipoprotein(a) [β₂-GPI-Lp(a)] levels with the presence and extent of coronary artery disease (CAD).
Methods: β₂-GPI-Lp(a) levels were measured in 116 patients with acute coronary syndromes (ACS), 72 patients with stable CAD and 100 control subjects.
Results: Compared to the control, β₂-GPI-Lp(a) levels (expressed after logarithmically transformation: ACS, 0.22±0.45 U/mL; stable CAD, 0.05±0.55 U/mL; control, −0.31±0.61 U/mL) significantly increased in both patients with ACS (p <0.001) and stable CAD (p <0.001). Univariate logistic regression analysis of risk factors revealed that the presence of β₂-GPI-Lp(a), ox-Lp(a) or Lp(a) was a strong risk factor for stable CAD [β₂GPI-Lp(a), OR 3.17, 95% CI 1.65, 6.07; ox-Lp(a), OR 2.54, 95% CI 1.33, 4.85; Lp(a), OR 3.00, 95% CI 1.56, 5.75; respectively], and especially for ACS [β₂-GPI-Lp(a), OR 5.38, 95% CI 2.97, 9.74; ox-Lp(a), OR 7.55, 95% CI 4.12, 13.84; Lp(a), OR 4.33, 95% CI 2.40, 7.80; respectively]. In multivariate analysis, adjusting for age, sex and plasma lipid levels, the presence of β₂-GPI-Lp(a) or Lp(a) was a risk factor for both stable CAD and ACS. Ox-Lp(a) was a risk factor only for ACS, while not for stable CAD. β₂-GPI-Lp(a) levels were found to be positively associated with Lp(a), ox-Lp(a), maximal stenosis and a number of vessel diseases in patients with ACS or stable CAD, respectively. Multiple linear regression analysis found that ox-Lp(a) and maximal stenosis accounted for 46.2% of the variation in β₂-GPI-Lp(a) levels.
Conclusions: Elevated levels of β₂-GPI-Lp(a) are associated with the presence and severity of CAD, and may be a strong risk factor for atherosclerosis.

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Aim: Serum γ-glutamyltransferase (GGT) is used as a marker of hepatic dysfunction. Recently, several studies reported that GGT is significantly associated with cardiovascular mortality and atherosclerosis. Adiponectin is known to play an important role in the development of atherosclerosis, but its physiologic role has yet to be fully determined. In this study, we investigated the relationships among serum GGT, adiponectin and arterial stiffness.
Methods: Of 4236 subjects recruited from 17 different medical centers in Seoul, Korea, 2846 subjects were enrolled in our study. The parameters of metabolic syndrome (MetS) were assessed in these subjects, and their plasma adiponectin levels and pulse wave velocity (PWV) were measured along with anthropometric and biochemical profiles, including GGT.
Results: The subjects were stratified into 3 groups according to GGT values. PWV values gradually increased and the adiponectin level decreased with GGT tertiles. Aortic PWV showed a significant correlation with age, SBP, FPG, but there was no correlation among aortic PWV, GGT and adiponectin. Peripheral PWV demonstrated a significant correlation with age, SBP, DBP, BMI, WC, FPG and GGT, but there was no correlation between peripheral PWV and adiponectin. In multiple logistic regression analysis after adjusting for risk factors, GGT was a significant contributor to increased peripheral PWV.
Conclusions: These findings indicate that serum GGT is independently associated with increased arterial stiffness, but there was no correlation between adiponectin and arterial stiffness in both males and females.

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Aim: Obstructive sleep apnea syndrome (OSAS) has been associated with high cardiovascular morbidity and mortality, and patients suffer from repeated episodes of hypoxia. Platelet-derived microparticles (PDMPs) are released via platelet activation by various agonists, including inflammatory cytokines or high shear stress. Plasminogen activator inhibitor -1 (PAI-1) is a fibrinolytic marker and soluble fibrin (SF) is a coagulation activation marker. We examined plasma levels of PDMPs, PAI-1 and SF in patients with OSAS. We also examined the effects of continuous positive airway pressure (CPAP) on plasma levels of PDMPs.
Methods: Full polysomnography (PSG) monitoring was performed on 27 patients. The apneahypopnea index (AHI) of 5 events/h or less than 30 events/h indicated mild to moderate OSAS, and an AHI of 30 events/h or more indicated severe OSAS. Plasma levels of PDMPs were measured using an ELISA kit, and PAI and SF were determined by a latex immunoassay. In addition, the effects of CPAP treatment were studied in 7 patients.
Result: The plasma level of PDMPs was significantly higher in patients with severe OSAS (15.8±10.4 U/mL) than normal controls (10.8±7.1 U/mL, p < 0.05) and patients with mild to moderate OSAS (9.2±3.5 U/mL, p < 0.05). The plasma levels of PDMPs correlated with the AHI (r = 0.39, p < 0.05). In addition, CPAP treatment decreased the plasma level of PDMPs (11.9±5.6 U/mL to 6.7±3.2 U/mL, p < 0.05).
Conclusions: Patients with OSAS might be at increased cardiovascular risk due to elevated PDMPs. Moreover a decrease in the plasma level of PDMPs by treatment with CPAP might reduce cardiovascular risk.

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