Yoshio Fujioka

Augmented Diurnal Variations of the Cardiac Renin-Angiotensin System in Hypertensive Rats

Abstract—There are several controversies concerning the enhanced gene expression of cardiac renin-angiotensin system components in spontaneously hypertensive rats (SHR) compared with their normotensive control Wistar-Kyoto (WKY) rats. We hypothesized that these discrepancies arise from circadian fluctuations in gene expression. We examined the circadian mRNA expression of renin, angiotensinogen, ACE, and angiotensin type 1a (AT1a) and type 2 (AT2) receptors in the hearts of SHR and WKY rats by real-time quantitative reverse transcription–polymerase chain reaction. The cardiac mRNA expression of the renin-angiotensin system components showed circadian oscillations in both SHR and WKY rats. The amplitudes of these circadian fluctuations were greater in the SHR than in the WKY rats. The mRNA levels of the renin-angiotensin system components were also increased in the SHR compared with the WKY rats at many time points (especially during the dark phase). However, the levels of ACE, AT1a receptor, and AT2 receptor mRNA in the SHR and WKY rats were almost the same during the late light phase. In contrast to mRNA expression, ACE activity was similar both at the time of maximum and minimum mRNA expression. The AT1 receptor antagonist candesartan upregulated AT1a receptor mRNA and downregulated ACE mRNA at specific time points only in the SHR group. Our findings of differential diurnal expression of cardiac renin-angiotensin system genes in SHR and WKY rats appear to explain the discrepancies between prior studies. However, the physiological relevance of the differential circadian mRNA expression of the renin-angiotensin system components remains to be elucidated.

Facilitated nitration and oxidation of LDL in cigarette smokers

Background  Cigarette smoking increases the risk of developing atherosclerosis and ischaemic heart disease. Smoking‐induced oxidative stress is considered to favour oxidation of low‐density lipoprotein (LDL) and subsequently promotes the atherogenic process. We investigated whether peroxynitrite, a reaction product of cigarette smoke, is involved in facilitated oxidation of LDL in smokers.

Increased circulating interleukin-18 in patients with congestive heart failure

Accumulating evidence suggests that proinflammatory cytokines such as tumour necrosis factor (TNF) α, interleukin (IL)-1β, and IL-6 are likely to be involved in the pathogenesis of advanced cardiac failure. Cytokine actions directly identified to date include promotion of systemic catabolism, myocardial depression, cardiac hypertrophy, and apoptosis of myocytes in congestive heart failure (CHF). IL-18, a new member of the IL-1 family, is a proinflammatory cytokine with multiple biologic functions.1 In concert with IL-12, IL-18 stimulates Th1 mediated immune responses; by itself, IL-18 can stimulate Th2 cytokine production. IL-18, originally named as an interferon γ inducing factor (IGIF),2 can induce TNFα and IL-6 in murine macrophages.3 Pomerantz and colleagues demonstrated that IL-18 is expressed in vascular endothelial cells and macrophages in human heart, and that IL-18 binding protein, which is derived from a gene distinct from the IL-18 receptor gene and can neutralise IL-18 actions, reduces human myocardial reperfusion injury after 30 minutes of ischaemia.4,5 We hypothesised that IL-18 might contribute to immune activation and cardiac dysfunction in congestive heart failure. In this study we examined serum concentrations of IL-18 in patients with CHF to examine whether the cytokine was involved in the pathophysiology of this syndrome. Subjects included 34 consecutively recruited patients (20 men and 14 women aged 42–83 years, mean 64 years) who had chronic, stable symptomatic heart failure representing New York Heart Association (NYHA) functional class II–IV for more than two …

Eicosapentaenoic Acid Improves Endothelial Function in Hypertriglyceridemic Subjects Despite Increased Lipid Oxidizability

BackgroundEpidemiologic investigations suggest that fish oil, which contains eicosapentaenoic acid (EPA), has favorable cardiovascular effects. Fish oil improves endothelial function in subjects with hypercholesterolemia or diabetes. However, controversy persists regarding relationships between primary hypertriglyceridemia and endothelial dysfunction. Moreover, lipoproteins are more susceptible to oxidation in vitro after incorporation of fish oil. MethodsWe determined the effects of EPA on serum lipids, susceptibility of low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) to oxidation, and endothelial function in hypertriglyceridemic (HTG) subjects. In 8 men with untreated primary hypertriglyceridemia (plasma triglyceride between 150 and 500 mg/dL) and 7 control subjects (triglyceride below 150 mg/dL), forearm blood flow (FBF) responses were tested. In HTG subjects, this was repeated 3 months after initiation of EPA (1800 mg / day). Cu2+-induced oxidation of VLDL and LDL was determined by serial measurement of conjugated dienes. We used lag time, which corresponded to the period when the lipoproteins were resistant to oxidation, as a parameter of oxidizability. FBF responses to acetylcholine and sodium nitroprusside were determined by strain-gauge plethysmography. ResultsPlasma triglyceride in HTG subjects fell 31% with EPA supplementation. Before EPA, VLDL and LDL lag times in HTG subjects were shorter than in control subjects. EPA further reduced lag time for VLDL but not LDL. The FBF response to acetylcholine (but not to nitroprusside) was significantly less in HTG subjects before EPA than in control subjects. EPA normalized the FBF response to acetylcholine. ConclusionsEPA improves endothelial function in HTG subjects despite increasing in VLDL oxidizability.

Transforming Growth Factor- β Signaling Enhances Transdifferentiation of Macrophages into Smooth Muscle–Like Cells

Hemopoietic cells or bone marrow–derived cells contribute to tissue formation, possibly by transdifferentiation into smooth muscle cells (SMCs) or myofibroblasts. In this study our goal is to examine the effects of transforming growth factor-β1 (TGF-β1) on the transdifferentiation of the monocyte/macrophage lineage into SMC-like cells. Using rat peritoneal exudate macrophages, we investigated the expression of smooth muscle–specific differentiation markers, such as α-smooth muscle actin, embryonic smooth muscle myosin heavy chain, and calponin. The treatment of macrophages with TGF-β1 enhanced the expression of SMC-specific markers at day 4; after 7 days in culture, a higher level of expression (approximately 3- to 5-fold) was detected on Western blots. In contrast, TGF-β1 decreased the expression of CD11b, which is a macrophage marker. Furthermore, we examined the effect of the TGF-β type 1 receptor inhibitor SB-431542 and a replication-defective adenovirus construct expressing Smad7 (Adeno-Smad7), which inhibits TGF-β signaling by interfering with the activation of other Smad proteins. Both SB-431542 and Adeno-Smad7 suppressed the expression of SMC-specific markers. These results indicated that TGF-β signaling is essential for the transdifferentiation of macrophages into SMC-like cells. Elucidating the mechanism by which macrophages transdifferentiate into SMC-like cells may reveal new therapeutic targets for preventing vascular diseases.

Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017

Toray Industries, Inc., Tokyo, Japan Department of Diabetes, Metabolism and Endocrinology, Chiba University Graduate School of Medicine, Chiba, Japan National Center for Geriatrics and Gerontology, Aichi, Japan Department of Internal Medicine and Cardiology, Gifu Prefectural General Medical Center, Gifu, Japan Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Iwate, Japan Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan Egusa Genshi Clinic, Hiroshima, Japan Department of Cardiovascular Medicine, Juntendo University, Tokyo, Japan Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan Biomedical Informatics, Osaka University, Osaka, Japan Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan Department of Community Health Systems Nursing, Ehime University Graduate School of Medicine, Ehime, Japan Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan Department of Vascular Surgery, Saitama Medical Center, Saitama, Japan Chief Health Management Department, Mitsui Chemicals Inc., Tokyo, Japan Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan Department of Neurology, Kita-Harima Medical Center, Hyogo, Japan Department of Internal Medicine, Mizonokuchi Hospital, Teikyo University School of Medicine, Kanagawa, Japan Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan Tsukasa Health Care Hospital, Kagoshima, Japan Faculty of Nutrition, Division of Clinical Nutrition, Kobe Gakuin University, Hyogo, Japan Department of Food and Nutrition, Faculty of Human Sciences and Design, Japan Women’s University, Tokyo, Japan 25 Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Medical Statistics, Toho University, Tokyo, Japan Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Laboratory Medicine, Jikei University Kashiwa Hospital, Chiba, Japan Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Department of Obstetrics and Gynecology, Aichi Medical University, Aichi, Japan 31 Department of Community Medicine, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Rinku General Medical Center, Osaka, Japan

Are Short Chain Fatty Acids in Gut Microbiota Defensive Players for Inflammation and Atherosclerosis

Intestinal flora (microbiota) have recently attracted attention among lipid and carbohydrate metabolism researchers. Microbiota metabolize resistant starches and dietary fibers through fermentation and decomposition, and provide short chain fatty acids (SCFAs) to the host. The major SCFAs acetates, propionate and butyrate, have different production ratios and physiological activities. Several receptors for SCFAs have been identified as the G-protein coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3), GPR43/FFAR2, GPR109A, and olfactory receptor 78, which are present in intestinal epithelial cells, immune cells, and adipocytes, despite their expression levels differing between tissues and cell types. Many studies have indicated that SCFAs exhibit a wide range of functions from immune regulation to metabolism in a variety of tissues and organs, and therefore have both a direct and indirect influence on our bodies. This review will focus on SCFAs, especially butyrate, and their effects on various inflammatory mechanisms including atherosclerosis. In the future, SCFAs may provide new insights into understanding the pathophysiology of chronic inflammation, metabolic disorders, and atherosclerosis, and we can expect the development of novel therapeutic strategies for these diseases.

Chylomicron remnant induces apoptosis in vascular endothelial cells.

Chylomicron remnant (CR) is a cholesteroland apoE-enriched particle derived from the lipolytic processing of intestinal chylomicron, and has been regarded as an atherogenic lipoprotein in postprandial hyperlipidemia.1,2 However, little is known about the mechanisms through which CR promotes atherosclerosis. Recent studies suggest that remnant lipoproteins induce vascular endothelial dysfunction assessed by measuring endothelium-dependent vasorelaxation.3 Endothelial injury and dysfunction induced by atherogenic lipoprotein are believed to play pivotal roles in atherogenesis. Apoptosis in endothelial cell is considered to be involved in this process.4,5 This hypothesis is supported by the findings that proatherosclerotic factors, such as oxidized low density lipoprotein (LDL), reactive oxygen species, and inflammatory cytokines, have all been shown to induce apoptosis of vascular endothelial cells.6,7 We postulated that CR may promote atherosclerosis by inducing apoptosis in vascular endothelial cells. To examine our hypothesis, we isolated CR and investigated whether CR induces apoptosis in vascular endothelial cells in vitro.

Candida parapsilosis endocarditis that emerged 2 years after abdominal surgery.

A 22-year-old man was hospitalized after 3 months of persistent fever and malaise. He had undergone abdominal surgery 24 months before admission. Echocardiography demonstrated two mobile pedunculated masses in the right ventricle. Multiple blood cultures were positive for Candida parapsilosis. After 4 weeks of miconazole treatment, the two masses were excised via a right atriotomy incision and the transtricuspid value approach. Histological examination revealed that they were fungal vegetation. Antifungal agents were continued for 1 year after surgery. The patient has remained well with no further symptoms for 3 years. This case suggests the necessity for careful evaluation of past history to avoid diagnostic delay in fungal endocarditis.

The effect of irradiation wavelengths and the crystal structures of titanium dioxide on the formation of singlet oxygen for bacterial killing

In inflammatory bowel diseases, interleukin-1β production is accelerated. Butyrate, a short chain fatty acid, plays an important role in inflammatory bowel diseases. We investigated the effect of butyrate on interleukin-1β production in macrophage and elucidated its underlying mechanism. We stimulated THP-1 cells, a human premonocytic cell line, by lipopolysaccharide alone and by butyrate with lipopolysaccharide. Butyrate with lipopolysaccharide increased interleukin-1β production more than lipopolysaccharide alone. Butyrate with lipopolysaccharide increased caspase-1 activity more than lipopolysaccharide alone. As for the phosphorylation pathway, PD98059 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor) decreased caspase-1 activity and interleukin-1β production to approximately 50% of the controls. Pertussis toxin (G protein-coupled signal transduction pathway inhibitor) also reduced interleukin-1β production to approximately 50%. Butyrate with lipopolysaccharide increased reactive oxygen species levels more than lipopolysaccharide alone. The addition of N-acetyl L-cysteine reduced reactive oxygen species levels to a level similar to that of lipopolysaccharide alone. Butyrate with lipopolysaccharide increased nitric oxide production more than lipopolysaccharide alone, and the addition of N-acetyl L-cysteine reduced the elevated amount of nitric oxide. In conclusions, butyrate enhances interleukin-1β production by activating caspase-1, via reactive oxygen species, the phosphorylation of MAPK, and G protein mediated pathways in lipopolysaccharide stimulated THP-1 cells.