Aim: Neovascularization is an important event in proliferative diabetic retinopathy (PDR), where various secretory proteins including multiple growth factors are considered to be involved in this process. We searched for secretory proteins expressed in a surgical specimen obtained from the eyes of patients with PDR.
Methods: We developed the oligo-cap signal sequence trap (SST) strategy which enables us to screen for secretory or membrane proteins from a minimal starting material. Using this method, we were able to screen a cDNA library constructed from a surgical specimen obtained from the eyes of the patients with PDR.
Results: Majority of the cloned cDNAs turned out to encode secreted protein acidic and rich in cystein (SPARC), strongly suggesting that SPARC is highly expressed in PDR. Analysis of vitreous fluid from various patients has shown that the concentration of SPARC protein is increased in patients with PDR. Furthermore, subretinal injection of recombinant SPARC adenovirus induced PDR-like changes in the rat eye.
Conclusions: Our results strongly suggested that SPARC is involved in the development of diabetic retinopathy (DR).

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Aim: Both oxidative stress and inflammation are known to play roles in the pathogenesis of cardiovascular disease. We investigated the relations between reactive oxygen metabolites (ROMs) and various inflammatory and metabolic parameters in a Japanese population.
Methods: We analyzed 48 male and 69 female subjects, aged 25 to 65 years, who underwent an annual health checkup in our university. Serum ROM level was assayed using a free radical elective evaluator. We also measured serum concentrations of high-sensitivity C-reactive protein (hsCRP), insulin, and high molecular weight (HMW) adiponectin.
Results: Although the serum ROM level in females (347±83 Carr U) was slightly higher than in males (333±53 Carr U), this was not statistically significant. In the 48 male subjects, the ROM level negatively correlated with age (r=-0.344, p=0.0161), and positively correlated with the hsCRP level (r=0.306, p=0.0338). In the 69 female subjects, the ROM level negatively correlated with serum creatinine (r=-0.293, p=0.0141), and positively correlated with insulin (r=0.278, p=0.0202), the insulin resistance index (r=0.286, p=0.0170) and hsCRP levels (r=0.487, p<0.0001). Stepwise multiple regression analysis revealed that serum hsCRP, creatinine, and age were independently correlated with the serum ROMs level (R²=0.365; F value highest for hsCRP). When the study subjects were divided into tertiles according to the ROM level, serum hsCRP was significantly different among the three groups: its level was highest in the highest tertile of ROMs (p<0.001).
Conclusion: These results suggest that the serum ROM level is closely associated with serum hsCRP in Japanese adult subjects.

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Aim: The aim of this study was to evaluate the significance of endothelial cell-derived microparticles (EDMP), angiopoietin-2 (Ang-2) and adiponectin in hyperlipidemic patients with and without type 2 diabetes mellitus, and to compare the two for the effects of eicosapentaenoic acid (EPA) on these markers.
Methods: One hundred and twenty-six hyperlipidemic patients with and without type 2 diabetes mellitus received EPA 1,800 mg daily, and 50 of the patients were non-diabetic.
Results: EDMP and Ang-2 levels prior to treatment were higher in diabetic patients than in non-diabetic patients, whereas adiponectin levels were lower in diabetics. When diabetic patients were classified into two groups on the basis of Ang-2 levels, the levels of all markers remained unchanged in those without a high Ang-2 level after EPA treatment. In contrast, all markers except for adiponectin were decreased significantly in diabetic patients with high Ang-2 levels after 6 months of EPA treatment. These diabetic patients with high Ang-2 levels displayed a more significant increase in adiponectin levels after EPA treatment than those who did not.
Conclusion: These results suggest that EPA possesses an adiponectin-dependent anti-atherosclerotic effect and may be beneficial for the prevention of vascular complications in diabetic patients with high Ang-2 levels.

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Aim: We attempted to explore interactions between smoking and the genetic polymorphism of 24 atherosclerosis-related candidate genes in systemic atherosclerosis.
Methods: The study comprised 1,503 consecutive autopsy cases. The male-to-female ratio was 1.16 and the average age at death was 80.3 years. Seventy percent of men and 22% of women were current or past smokers. The degree of atherosclerosis in 10 arteries was semi-quantitatively assessed. Melting curve analysis analyzed 34 single nucleotide polymorphisms (SNPs) of 24 genes.
Results: Twenty-four SNPs did not interact with smoking on atherosclerosis, while 7 SNPs interacted in one artery and 2 SNPs in two arteries. The genotypes of MTHFR 677C>T and smoking significantly interacted in four arteries, including the common carotid artery, common and external iliac arteries, and femoral artery. The odds ratios of smoking on atherosclerosis were high (3.034.63) in TT homozygotes, intermediate (1.755.24) in heterozygotes, and low (1.752.63) in CC homozygotes in systemic arteries except for cerebral and coronary arteries.
Conclusion: MTHFR 677 TT homozygotes are more likely to develop atherosclerosis than heterozygotes or CC homozygotes, if they smoke. Thus, smoking cessation is more important in the prevention of atherosclerosis in MTHFR 677 TT homozygotes.

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Aim: To investigate the association between arterial stiffness (present with brachial-ankle pulse wave velocity (baPWV)) and metabolic syndrome (MetS) in a population-based study of middle-aged Chinese.
Methods: MetS was defined using the AHA/NHLBI criteria. A total of 1,018 subjects aged 40 years and over were recruited in 2004. Homeostasis model assessment was applied to estimate the degree of insulin resistance (HOMA-IR). The baPWV was divided into four groups by quartiles.
Results: The prevalence of MetS and its individual components increased by the increase in baPWV quartiles. After adjusting for age, BMI, HOMA-IR, smoking, alcohol drinking, betel nut chewing, and physical activity status, multiple logistic regression revealed that baPWV groups were significantly associated with MetS. Compared with the lowest baPWV quartile, the adjusted odds ratio of having MetS in baPWV quartile II, III, IV was 2.10 (1.034.28), 4.48 (2.169.26), 10.4 (4.5324.0) in men, and 4.20 (1.4712.0), 14.6 (5.2240.6), 16.3 (5.4848.2) in women, respectively. The prevalence of MetS increased with the increase of age, HOMA-IR, and BMI groups. The optimal cut-off values of baPWV for MetS were 1,539 cm/sec in men and 1,482 cm/sec in women, respectively.
Conclusions: In addition to insulin resistance and obesity, baPWV was strongly related to MetS in middle-aged Taiwan Chinese. The cut-off value of baPWV for cardiovascular disease differed between genders.

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Aim: To verify the clinical diagnostic criteria for metabolic syndrome (MetS-Criteria) for Japanese (Japanese-Criteria) from the viewpoint of reference intervals (RIs) of metabolic factors.
Methods: In healthy subjects selected from 1,379 males and 1,528 females aged 2065 years, generation-and gender-specific RIs of metabolic factors were determined. Then, from the upper or lower limits of the RIs, new MetS-Criteria were tentatively set (New-Criteria).
Results: RIs of some metabolic factors were associated with gender- and/or generation-specific differences. In both genders, the New-Criteria for subjects in their 40s and over (older adults) were comparable to the Japanese-Criteria, whereas the New-Criteria for these in their 30s and less (younger adults) were not. Levels of cut-off values in the New-Criteria for younger adults were mostly between those of the Japanese-Criteria and recently established MetS-Criteria for adolescents. The prevalence of metabolic syndrome estimated by the Japanese-Criteria and the New-Criteria well corresponded in older adults but significantly differed in younger adults.
Conclusion: MetS-Criteria prepared on gender- and generation-specific bases may be necessary. The Japanese-Criteria, which may still have room for minor changes, seem to be valid at least for older adults; however, new MetS-Criteria should be established for younger adults.

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Aim: Mice lacking apolipoprotein A-V (apoA-V) displayed an increase in serum triglyceride (TG) levels; however, the correlation of apoA-V levels with TG levels in humans is controversial, and the exact mechanism by which apoA-V affects TG levels is unclear. The aim of the present study was to clarify the impact of apoA-V on the lipoprotein subclass profile in preadolescent children, which has not been studied.
Method: The study subjects were 178 (89 male, 89 female) 4th grade elementary school children (mean±SD: 9.5±0.5 years old). ApoA-V levels were determined by an enzyme-linked immunosorbent assay, and the lipid component of each lipoprotein fraction and their particle sizes were measured by HPLC.
Results: Levels of apoA-V showed no gender difference in preadolescent children, and were not affected by anthropometric variables. ApoA-V had a negative association with serum TG levels and TG levels in each lipoprotein fraction, and a positive association with HDL-C. In particular, apoA-V appears to contribute to the increase in cholesterol levels in the larger HDL fraction.
Conclusions: It was suggested that apoA-V is a potent modulator of HDL and VLDL components in preadolescent children.

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Aim: Heparin cofactor II (HCII) specifically inactivates thrombin action at the injured vascular wall. We have reported that HCII is a protective factor against coronary in-stent restenosis and carotid atherosclerosis; however, it is unclear whether there is any correlation between plasma HCII levels and the development of peripheral arterial disease (PAD).
Methods: Plasma HCII activity and the ankle brachial pressure index (ABI) were determined in 494 elderly subjects with cardiovascular risk factors. PAD was diagnosed by ABI below 0.9, and 62 subjects were diagnosed with PAD. The relationship between factors that affect cardiovascular events and the prevalence of PAD was statistically evaluated.
Results: Mean HCII activity in PAD subjects was significantly lower than in non-PAD subjects (87.5±19.7% v.s. 94.6±17.8%, p=0.009). Multivariate logistic regression analysis showed that age (odds ratio [OR]: 1.062, p=0.0016), current smoking (OR 3.028, p=0.002) and diabetes mellitus (OR 2.656, p=0.008) were independent and progressive determinants of PAD. In contrast, HCII was an independent inhibitory factor of PAD (OR: 0.982, p=0.048).
Conclusions: Plasma HCII activity is inversely related to the prevalence of PAD. HCII may function as the sole protective factor against PAD in elderly people with cardiovascular risk factors.

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Aim: Telmisartan, an angiotensin II receptor blocker (ARB), was reported to have partial peroxisome proliferator-activated receptor gamma (PPARγ) activity in vitro. Also, adipocyte-derived protein adiponectin, especially its high molecular weight (HMW) form, has been reported to have beneficial effects on insulin resistance and atherosclerosis. We investigated the effects of 3-month telmisartan therapy on various metabolic parameters, including serum HMW adiponectin and high-sensitivity C-reactive protein (hs-CRP) levels in male hypertensive subjects with abdominal obesity.
Methods: This study included 19 Japanese male hypertensive subjects, aged 51.2±7.6 (mean±SD) years, and body mass index 27.7±4.1 kg/m². In these subjects, 14 were naive to telmisartan treatment (40.0±15.7 mg daily), and 5 were changed from other ARBs to telmisartan. Serum HMW adiponectin concentration was assayed using HMW-selective ELISA kit.
Results: In all 19 subjects, systolic/diastolic blood pressure (BP) decreased from 153/98 to 134/85 mmHg (p<0.001 for both). Serum HMW-adiponectin level increased from 2.06±0.81 to 2.40±0.96 μg/mL (+16.4%, p=0.017). Body weight, glucose, insulin, lipids and hs-CRP did not change during the study period, and there were no adverse effects in any subject. In the newly administered group (n=14), the results were almost the same: BP decreased from 155/98 to 134/84 mmHg (p=0.0015 for both), and serum HMW-adiponectin level increased from 2.07±0.68 to 2.39±0.99 μg/mL (+15.5%, p=0.089).
Conclusion: These data suggest that telmisartan therapy is efficient for controlling BP, and may exert beneficial effects on HMW adiponectin in male hypertensive subjects with abdominal obesity.

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