Shosuke Satake

Induction of Macrophage VEGF in Response to Oxidized LDL and VEGF Accumulation in Human Atherosclerotic Lesions

The interaction between macrophages and oxidatively modified low density lipoprotein (Ox-LDL) appears to play a central role in the development of atherosclerosis, not only through foam cell formation but also via the induction of numerous cytokines and growth factors. The current study demonstrated that Ox-LDL upregulated vascular endothelial growth factor (VEGF) mRNA expression in RAW 264 cells, a monocytic cell line, in a time- and concentration-dependent manner and that Ox-LDL stimulated VEGF protein secretion from the cells. Lysophosphatidylcholine, a component of Ox-LDL, also enhanced VEGF mRNA expression in RAW 264 cells and VEGF secretion from RAW 264 cells, with a maximal effect at a concentration of 10 micromol/L lysophosphatidylcholine. Immunohistochemical studies showed that human early atherosclerotic lesions exhibited intense VEGF immunoreactivity in subendothelial macrophage-rich regions of the thickened intima. In atherosclerotic plaques, VEGF staining was also observed in foam cell-rich regions adjacent to the lipid core or the neovascularized basal regions of plaque consisting predominantly of smooth muscle cells. High-power-field observation revealed that VEGF was localized in the extracellular space as well as at the macrophage cell surface. These observations suggest the possible involvement of Ox-LDL in the development of human atherosclerosis through VEGF induction in macrophages.

Inhibition of angiogenesis on glycated collagen lattices

Summary Advanced glycation endproduct (AGE) accumulation in extracellular matrix proteins has been demonstrated in diabetic patients with a significant correlation with the severity of diabetic complications. AGE accumulation induces matrix protein cross-link formation, resulting in an increased stiffness of matrix fibres and the reduction of the susceptibility of matrix proteins to proteolytic degradation. We examined whether glycation-induced collagen cross-linking may affect vascular endothelial cell behaviours such as invasion, proliferation and differentiation, using the in vitro angiogenesis model of capillary-like structure formation in three-dimensional matrices of collagen type I. Endothelial cells cultured on collagen gel with angiogenic factors (the combination of fibroblast growth factor-2 and vascular endothelial growth factor) invaded the underlying collagen matrix, and organized capillary-like cord structures in the gel. We found that endothelial cell invasion into glycated collagen gel was significantly attenuated without any effect on proteinase activity including cell-associated plasminogen activator and matrix metalloproteinase in the conditioned medium. In addition, subsequent capillary-like cord formation was also inhibited in glycated collagen gel. In contrast, endothelial cell proliferation was enhanced on glycated collagen gel with or without angiogenic factors compared with control collagen gel. These results suggest that the structural alterations of extracellular matrix proteins through the glycation-induced cross-link formation affect the interaction between endothelial cell and extracellular matrix, resulting in the impairment of an adequate neovascularization in diabetic patients. [Diabetologia (1998) 41: 491–499]

Up-regulation of vascular endothelial growth factor in response to glucose deprivation

Vascular endothelial growth factor (VEGF), also known as a vascular permeability factor (VPF), is an endothelial specific mitogen and is a potent inducer of angiogenesis. Recently it has been reported that hypoxia induces VEGF mRNA expression in various cells. Since both oxygen and glucose are required for efficient production of energy, we examined the effect of glucose deprivation on VEGF mRNA expression and VEGF protein production in U‐937 (a human monocytic cell line) cells. Both the mRNA expression and secretion of VEGF increased after exposure to low glucose. Addition of L‐glucose, the L‐stereoisomer of D‐glucose, did not prevent the up‐regulation of VEGF expression. The conditioned medium from glucose‐deprived cells, followed by supplementation with glucose, did not up‐regulate VEGF mRNA expression in U‐937 cells. The low glucose‐induced VEGF mRNA expression returned to the control level after supplementation with D‐glucose. Furthermore, oligomycin, a mitochondrial ATP synthase inhibitor, increased VEGF protein production. The results suggest that the up‐regulation of VEGF mRNA in U‐937 cells in response to glucose deprivation is not mediated by autocrine factors from the cells nor is the osmotic change of the medium mediated by the deficiency of glucose metabolism in the cells. Our results also suggest that the intracellular ATP depletion due to glucose deprivation may be one of the causes for increased VEGF mRNA expression. We speculate that local hypoglycemia may act as an essential trigger for angiogenesis through the VEGF gene expression.

Validity of the Kihon Checklist for assessing frailty status

The Kihon Checklist is extensively used in Japan to identify elderly persons who are at risk of requiring support/care. We aimed to determine whether or not the Kihon Checklist can estimate frailty status defined by the Cardiovascular Health Study criteria.

English translation of the Kihon Checklist.

Since the introduction of the long-term care insurance (LTCI) system in 2000, the number of older persons with LTCI service requirement has been increasing in Japan. Therefore, the Japanese Ministry of Health, Labor and Welfare started the Care Prevention Programs in 2006 to prevent frailty and disability of older persons, and introduced the “Kihon Checklist” (KCL) to identify vulnerable older adults as those at a higher risk of becoming dependent. The KCL has 25 yes/no questions divided into seven domains: activities of daily living, physical strength, nutrition, oral function, isolation, memory and mood, and has been used for screening frail older adults. Indeed, many studies have shown that the KCL was able to predict older persons who required the LTCI service and to assess frailty. However, several reports used different English translations of the KCL in their manuscripts. Additionally, Sampaio et al. created the Portuguese version of the KCL, and used it to assess frailty in Brazilian older adults, showing that the KCL can be used for elderly care in other countries as well. Therefore, we decided to create the official version of the KCL. The translation of the KCL into English was carried out by two people bilingual in Japanese and English. Next, the English version of KCL was back-translated into Japanese by one of the members of the Working Group on Frailty. This process was used to verify whether or not the KCL back-translation contained any incorrect expressions compared with the original Japanese version of the KCL. We then ensured the similarity of the contents between the original and back-translated versions of the KCL. After we approved the final version of the KCL, we asked a native English speaker to check the English (Table 1). We hope that this English version

Differential subtypes of diabetic older adults diagnosed with Alzheimer's disease

The clinical management of diabetic elderly patients with Alzheimers disease (AD) is hindered by several difficulties. The present study aimed to clarify the clinical characteristics and pathophysiological properties of AD in diabetic older adults.

Implications of frailty screening in clinical practice

Purpose of review Many frailty screening instruments have been proposed due to the lack of consensus on a unified operational definition of frailty. This review reports on recent frailty screening tools in addition to revisiting the frailty concept. Recent findings Although there are two representative frailty models, both have issues that prevent them from being implemented in clinical settings despite their remarkable advantages. Due to their different characteristics, these models are thought to be complementary rather than substitutive. The recent introduction of frailty identification into primary care and specific clinical settings has led to both a focus on its importance and the development of new screening methods. Summary The phenotype model is rather faithfully based on biological change with aging, while the deficit model comprehensively captures risk of disability. Most of the current frailty screening tools are based on these models. Screening tools based on the former model primarily capture declines in physical functions, whereas screening tools based on the latter model involve questionnaires that examine functional impairments in multiple domains. Implementation of a model in a clinical setting depends on both the model characteristics and the clinical settings.

Characteristics of physical prefrailty among Japanese healthy older adults

The purpose of the present study was to clarify the characteristics of frailty at an early stage (prefrailty) in a healthy elderly Japanese population.

Chapter 2 Epidemiology of sarcopenia: Epidemiology of sarcopenia

• Based on the definitions of sarcopenia provided in the European Working group on Sarcopenia in Older People (EWGSOP) and International Working group on Sarcopenia criteria, 1–29% and 14–33% of individuals aged ≥65 years residing around a given region and care facilities, respectively, meet the criteria for sarcopenia. The prevalence of sarcopenia can be estimated at 6–12% from the large-scale studies.

Prevalence of frailty among community-dwellers and outpatients in Japan as defined by the Japanese version of the Cardiovascular Health Study criteria: Letters to the Editor

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