NADPH oxidases (NOX) are enzymes that catalyze the production of reactive oxygen species (ROS). Four species of NOX catalytic homologs (NOX1, NOX2, NOX4, and NOX5) are reportedly expressed in vascular tissues. The pro-atherogenic roles of NOX1, NOX2, and their organizer protein p47^ph°^x were manifested, and it was noted that the hydrogen peroxide-generating enzyme NOX4 possesses atheroprotective effects. Loss of NOX1 or p47^ph°^x appears to ameliorate murine aortic dissection and subsequent aneurysmal diseases; in contrast, the ablation of NOX2 exacerbates the aneurysmal diseases. It is possible that the loss of NOX2 activates inflammatory cascades in macrophages in the lesions. Roles of NOX5 in vascular functions are currently undetermined, owing to the absence of this enzyme in rodents and the limitation of the experimental procedure. Thus, it is possible that the NOX family of enzymes exhibits heterogeneity in the atherosclerotic diseases. In this aspect, subtype-selective NOX inhibitor may be promising when NOX systems serve as a molecular target for atherosclerotic and aneurysmal diseases.

Although the human liver comprises approximately 2.8% of the body weight, it plays a central role in the control of energy metabolism. While the biochemistry of energy substrates such as glucose, fatty acids, and ketone bodies in the liver is well understood, many aspects of the overall control system for hepatic metabolism remain largely unknown. These include mechanisms underlying the ascertainment of its energy metabolism status by the liver, and the way in which this information is used to communicate and function together with adipose tissues and other organs involved in energy metabolism.

This review article summarizes hepatic control of energy metabolism via the autonomic nervous system.

Statin treatment to reduce low-density lipoprotein cholesterol (LDL-C) is associated with the prevention of cardiovascular events in Western patients. Similar results have been reported in studies conducted in Japan. However, the dose of statins and the degree of LDL-C reduction achieved with statins are different between Asian and Western patients. In addition, there are limited data regarding racial differences in response to statins. In this review, racial differences between Asians and Westerners in response to statins are described.

Aim: We examined the effects of mild hyperbaric oxygen on the properties of the soleus muscle in rats with metabolic syndrome.

Methods: Five-week-old metabolic syndrome (SHR/NDmcr-cp, cp/cp) rats were divided into normobaric (CP) and mild hyperbaric oxygen (CP-H) groups (n=5/group). In addition, 5-week-old Wistar rats were assigned as the normobaric control (WR) group (n=5). The CP-H group was exposed to 1.25 atmospheres absolute with 36% oxygen for 3 h daily for 16 weeks. Succinate dehydrogenase (SDH) activity and mRNA levels of peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α) in the soleus muscle were examined. The fiber type composition, cross-sectional areas, and SDH staining intensity in the soleus muscle were also examined.

Results: The CP-H group showed lower fasting and nonfasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, insulin, and systolic blood pressure levels; higher adiponectin levels; and higher SDH activity and mRNA levels of Pgc-1α in the muscle than the CP group. Compared with the CP group, the CP-H group had a lower percentage of type I fibers and observed type IIA fibers in the muscle. The CP-H group also had higher SDH staining intensity of type Ⅰ and type IIC fibers in the muscle than the CP group. No differences in these values were observed in the muscles of the WR and CP-H groups.

Conclusion: Mild hyperbaric oxygen inhibited growth-related increase in blood glucose levels and decrease in muscle oxidative capacity of rats with metabolic syndrome because of improved oxidative metabolism.

Aim: Inflammation is highlighted in the pathogenesis and destabilization of atherosclerotic lesions. Noninvasive identification of inflammation of atherosclerotic lesions has been challenging. 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is a useful technique for detecting inflamed atherosclerotic plaques in vivo. However, it is time consuming, expensive, and accompanied by radiation. Therefore, we investigated the relationship between levels of circulating inflammatory markers and the degree of inflammation of atherosclerotic plaques shown by 18F-FDG uptake. We aimed to identify high-risk patients with inflamed, unstable atherosclerotic plaques on the basis of the determination of inflammatory markers.

Methods: The study included 37 patients, 21 with high-grade stenosis of internal carotid artery (ICA group) and 16 with occlusion of common femoral artery (CFA group), who underwent endarterectomy. Mean age of the study population was 69.43±6.2 years. Eight out of 21 patients with ICA stenosis and all patients with CFA occlusion were symptomatic. In all patients before endarterectomy, 18F-FDG-PET imaging was performed and blood samples were obtained for determination of circulating inflammatory markers: high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), interleukins, and selectins. Both groups were compared with a sex- and age-matched control group composed of 27 healthy volunteers.

Results: 18F-FDG uptake, calculated by target-to-background ratio (TBR) was not significantly different between the groups. Levels of inflammatory markers were elevated, and there were no significant differences between ICA and CFA groups, with an exception of interleukin 6 (IL-6) levels, which was higher in the ICA group (3.2±2.5 ng/L vs. 1.8±1.3 ng/L, p＜0.05). There was a positive interrelationship between 18F-FDG-PET and most of the systemic inflammatory markers: hsCRP (r=0.417, p=0.010), IL-6 (r=0.603, p＜0.001), and TNF-α (r=0.374, p=0.023). However, correlation between 18F-FDG-PET and P-selectin, E-selectin, and t-PA was not found.

Conclusion: Our study showed that an interrelationship exists between the intensity of inflammatory process of atherosclerotic lesions shown by FDG uptake and circulating inflammatory markers. Therefore, the determination of circulating inflammatory markers can have a potential to identify individuals with unstable, inflamed atherosclerotic plaques.

Aim: To investigate whether body adiposity index (BAI; hip/height^1.5–18), pediatric BAI (BAIp; hip/height^0.8 – 38), and other hip/height^P ratios are useful in obese children.

Method: Ninety obese Japanese children, 55 boys and 35 girls, who visited our University Clinic, were enrolled. The age was 9.92±2.6 (mean±SD) years, and the percentage overweight (POW) was 51.6±18.8%. We set the power value of the hip/height^P 0, 0.5, 0.8, 1, 1.5, and 2 and studied the association with overweight indices, biochemical data, and fat area measured by computed tomography. Waist, waist/height ratio, and waist/hip ratio were also evaluated.

Results: Hip/height and hip/height^0.8 (BAIp) were more closely correlated with POW, body mass index percentile, and percentage body fat than hip/height^1.5 (BAI). The correlation coefficient of hip/height with POW (r =0.855) was the highest among the studied hip/height^P indices. The approximate line to predict POW was 411×hip/height–207. The waist/height was also highly correlated with POW (r=0.879). Hip and hip/height^0.5 were more closely correlated with visceral fat area than hip/height, BAIp, and hip/height^1.5. Hip and hip/height^0.5 were significantly correlated with insulin. Only hip was also significantly associated with dyslipidemia. All hip/height^P indices were not significantly correlated with alanine aminotransferase (ALT). Waist was significantly correlated with serum lipids, ALT, and insulin.

Conclusion: Hip/height and BAIp are better markers for overweight (adiposity) in obese children than BAI. However, hip/height, BAIp, and BAI are not useful to predict metabolic complications. Waist appears to be the best index for obese children overall at this time.

Aim: Atherosclerosis is a chronic inflammatory disease, which leads to thrombosis and acute coronary syndrome. Matrix metalloproteinase-9 (MMP-9) is involved in the stability of the extracellular matrix (ECM) and atherosclerosis plaque. Until now, it is established that lipopolysaccharide (LPS) and norepinephrine (NE) are associated with the pathological process of atherosclerosis. However, the combined effect of LPS and NE on MMP-9 is unclear. We investigated the combined effect of LPS and NE on MMP-9 expression in human monocytes and the mechanism involved in the process.

Methods: THP-1 cells were cultured and treated with LPS and/or NE. MMP-9 and TIMP-1 gene and protein expression were detected by real time PCR and ELISA, respectively. MMP-9 activity was detected by gelatin zymography. Adrenoceptor antagonists and MAPKs inhibitors were used to clarify the mechanism. Pathway-related proteins were detected by Western blot.

Results: We found that NE enhances LPS-induced MMP-9 and TIMP-1 expression as well as MMP-9 activity in THP-1 cells. This effect is reversed by the beta (β)-adrenoceptor antagonist propranolol, extracellular signal-regulated kinases (ERK) inhibitor U0126, and c-Jun N-terminal kinase (JNK) inhibitor SP600125. NE enhances LPS-induced ERK/JNK phosphorylation. NE up-regulates LPS-induced c-Fos expression, which is counteracted by propranolol, U0126, and SP600125. Furthermore, c-Fos silence reverses the effect of NE on MMP-9 activity.

Conclusions: Our results suggest that NE enhances LPS-induced MMP-9 expression through β-adrenergic receptor and downstream ERK/JNK-c-Fos pathway. This study may help us to understand the combined effect and mechanism of NE/LPS on MMP-9 expression.

Aim: Although warfarin remains important despite the widespread use of nonvitamin K antagonist oral anticoagulants (NOACs), to date, the reality of warfarin use in the “NOACs era” is unclear. This multicenter observational study aimed to clarify the key factors contributing to warfarin treatment stability.

Methods: The practical use of warfarin, stability of warfarin therapy, and factors contributing to this stability were investigated in community-based hospitals through a real-world study. Clinical data were retrospectively extracted from the medical records of warfarin-treated Japanese patients (age, 71.3±5.5 years) with atrial fibrillation (AF), prosthetic heart valve, or other concerns requiring anticoagulation. Treatment stability was considered as time in therapeutic range of international normalized ratio of prothrombin time (TTR: %). The factors contributing to TTR were investigated, including CHADS₂ score components.

Results: Mean CHADS₂ score was highest (1.38±0.88, p＜0.001), and most CHADS₂ score components in addition to hepatorenal dysfunction were factors contributing to the low TTR in patients with AF (n=176). The similarity was found in overall patients who were prescribed warfarin (n= 518). TTR decreased according to the CHADS₂ score component accumulation. Gender, dose and prescription interval of warfarin, and co-administration of antiplatelet agents did not correlate with the low TTR.

Conclusions: This retrospective study demonstrated that the CHADS₂ score component accumulation and hepatorenal dysfunction are factors significantly contributing to the low TTR, which is indicative of poor warfarin treatment stability, in patients such as those with AF.

Aim: We investigated the safety and efficacy of a long-term combination therapy with fenofibrate and ezetimibe in Japanese patients with combined hyperlipidemia, in comparison with fenofibrate or ezetimibe alone.

Methods: The study was a three-arm parallel-group, open-label randomized trial. Eligible patients were assigned to a combination therapy with fenofibrate (200 mg/day in capsule form or 160 mg/day in tablet form) and ezetimibe (10 mg/day), the fenofibrate monotherapy, or the ezetimibe monotherapy, which lasted for 52 weeks. The changes in serum low-density lipoprotein (LDL) cholesterol and triglycerides were the primary outcomes.

Results: A total of 236 patients were assigned to one of the three treatments, and the number of patients included in the final analysis was 107 in the combination therapy, 52 in the fenofibrate monotherapy, and 51 in the ezetimibe monotherapy. Mean±SD changes in LDL cholesterol were -24.2%±14.7% with combination therapy, -16.0%±16.0% with fenofibrate alone, and -17.4%± 10.1% with ezetimibe alone. The combination therapy resulted in a significantly greater reduction in LDL cholesterol as compared with each monotherapy (p＜0.01 for each). The corresponding values for triglycerides were -40.0%±29.5%, -40.1%±28.7%, and -3.4%±32.6%, respectively. Fenofibrate use was associated with some changes in laboratory measurements, but there was no differential adverse effect between the combination therapy and fenofibrate monotherapy.

Conclusion: The combination therapy with fenofibrate and ezetimibe substantially reduces concentrations of LDL cholesterol and triglycerides and is safe in a long-term treatment in Japanese patients with combined hyperlipidemia.