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ABSTRACT: We review the critical roles of peroxiredoxin (PRDX) 4 in inflammatory diseases. The PRDX family, a new family of proteins with an antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. The function of these enzymes, which include at least six distinct PRDX genes expressed in mammals, still remains unclear. Especially, in contrast to the intracellular localization of other family members, PRDX4 is the only known secretory form located in the extracellular space and exerts its protective function against oxidative damage by scavenging reactive oxygen species in the vascular vessels. To date, however, it is not clear whether or how PRDX4 expression affects various diseases in vivo. More recently, we generated human PRDX4 (hPRDX4) transgenic (Tg) mice, and, for the first time, established a type 1 diabetes mellitus model induced by a single high dose of streptozotocin on Tg mice. Our published data demonstrate that streptozotocin-treated Tg mice, which overexpress hPRDX4 in pancreatic islets, can protect pancreatic beta-cells against streptozotocin-induced injury (insulitis) by suppressing increased oxidative stress and inflammatory signaling activation. These observations indicate that Tg mice could become a useful animal model to study the relevance of oxidative stress to inflammation, and that a specific accelerator of PRDX4 might prove to be a potential therapeutic agent for ameliorating various chronic inflammatory diseases.
Journal of UOEH 03/2012; 34(1):27-39.
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Sohsuke Yamada, Yan Ding,
Akihide Tanimoto,
Ke-Yong Wang,
Xin Guo,
Zhi Li,
Takashi Tasaki,
Atsunori Nabesima,
Yoshitaka Murata,
Shohei Shimajiri,
Kimitoshi Kohno,
Hidenori Ichijo,
Yasuyuki Sasaguri
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ABSTRACT: The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis.
We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1(-/-)/apoE(-/-)) and analyzed atherosclerosis in ASK1(-/-)/apoE(-/-) mice fed a high-cholesterol diet for 12 weeks. ASK1(-/-)/apoE(-/-) mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE(-/-) mice. Bone marrow transplantation from ASK1(-/-) or wild-type to apoE(-/-) mice confirmed the above observation that the recipient mice of ASK1(-/-) donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors.
These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development.
Arteriosclerosis Thrombosis and Vascular Biology 07/2011; 31(7):1555-64. · 6.37 Impact Factor
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Pathology International 06/2011; 61(6):387-9. · 1.62 Impact Factor
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ABSTRACT: A case of non-functioning adrenocortical adenoma combined with myelolipoma and endothelial cysts is reported. A 72-year-old Japanese female was noticed to have right renal and left adrenal tumors by an abdominal CT scan. At surgery, the mildly enlarged left adrenal gland contained a well-demarcated tumor. Macroscopically, it was yellowish to dark red or grayish in color, and was characterized by geographic appearance on the cut surface. Histopathological examination revealed a solid proliferation of clear or compact cells and a normal rim of adrenal gland, coexisting with vascular multiple cysts and myelolipomas. The cysts were filled with clotted blood, fibrinous material, or thrombi, and were partially lined with flattened endothelial cells with focal papillary hyperplasia, which were immunohistochemically positive for CD31 and CD34. These cystic walls were often thickened with hyalinized fibrosis and calcification, and were connected to myelolipomatous elements. To our knowledge, this is the first case report of adrenocortical adenoma associated with myelolipoma and endothelial cysts. It is probable that the extensive degeneration in adenoma might induce myelolipomatous metaplasia and cystic vascular formation.
Pathology - Research and Practice 03/2011; 207(3):192-6. · 1.21 Impact Factor
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ABSTRACT: We describe the clinicopathological features of a case of total anomalous pulmonary vein drainage (TAPVD) associated with atresia of the common pulmonary vein (ACPV). A male Japanese infant born at 37 weeks of gestation demonstrated apnea and severe respiratory acidosis immediately after delivery. The patient died of hypoxemic respiratory failure 6 days after birth despite the initiation of artificial ventilation and administration of a surfactant. Autopsy showed the bilateral inferior pulmonary veins joined with a blind confluence, representing ACPV, accompanied by atresia of the left superior pulmonary vein. Moreover, the anomalous and small right superior pulmonary vein drained into the superior vena cava, consistent with partial and supracardiac type TAPVD. A histological examination of the lungs exhibited diffuse dilation of the lymphatic channels in the peribronchial, interlobular, hilar and focally, subpleural areas. The channels were lined with flattened endothelium which was immunohistochemically positive for D2-40. These findings conformed to a secondary form of pulmonary lymphangiectasis due to the congenital cardiovascular anomalies, including TAPVD and ACPV. To the authors' knowledge, this is the first case of TAPVD associated with ACPV, atresia of left superior pulmonary vein and pulmonary lymphangiectasis.
Pathology International 02/2011; 61(2):93-8. · 1.62 Impact Factor
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Ke-Yong Wang,
Akihide Tanimoto,
Xin Guo,
Sohsuke Yamada,
Shohei Shimajiri,
Yoshitaka Murata, Yan Ding,
Masato Tsutsui,
Seiya Kato,
Teruo Watanabe,
Hiroshi Ohtsu,
Ken-Ichi Hirano,
Kimitoshi Kohno,
Yasuyuki Sasaguri
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ABSTRACT: Histamine and histamine receptors are found in atherosclerotic lesions, and their signaling and subsequent proatherogenic or proinflammatory gene expression are involved in atherogenesis. In the present study, we generated apolipoprotein E (apoE) and histamine synthesizing histidine decarboxylase double knockout (DKO) mice on a C57BL/6J (wild-type mice) background to clarify the roles of histamine in atherosclerosis.
Wild-type, apoE knockout (KO), and DKO mice were fed a high-cholesterol diet to analyze hyperlipidemia-induced atherosclerosis. Compared with wild-type mice, apoE-KO mice showed increased expression of histamine and its receptors, corresponding to increased atherosclerotic lesion areas and expression of inflammatory regulators, such as nuclear factor-κB, scavenger receptors, inflammatory cytokines, and matrix metalloproteinases. Histamine deficiency after deletion of histidine decarboxylase reduced atherosclerotic areas and expression of a range of the inflammation regulatory genes, but serum cholesterol levels of DKO mice were higher than those of apoE-KO mice.
These results indicate that histamine is involved in the development of atherosclerosis in apoE-KO mice by regulating gene expression of inflammatory modulators, an action that appears to be independent of serum cholesterol levels. In addition to acute inflammatory response, histamine participates in chronic inflammation, such as hyperlipidemia-induced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis.
Arteriosclerosis Thrombosis and Vascular Biology 01/2011; 31(4):800-7. · 6.37 Impact Factor
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Ke-Yong Wang,
Akihide Tanimoto,
Sohsuke Yamada,
Xin Guo, Yan Ding,
Teruo Watanabe,
Takeshi Watanabe,
Kimitoshi Kohno,
Ken-Ichi Hirano,
Hideo Tsukada,
Yasuyuki Sasaguri
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ABSTRACT: Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-d-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH.
American Journal Of Pathology 08/2010; 177(2):713-23. · 4.89 Impact Factor
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Yan Ding,
Sohsuke Yamada,
Ke-Yong Wang,
Shohei Shimajiri,
Xin Guo,
Akihide Tanimoto,
Yoshitaka Murata,
Shuji Kitajima,
Teruo Watanabe,
Hiroto Izumi,
Kimitoshi Kohno,
Yasuyuki Sasaguri
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ABSTRACT: Peroxiredoxin 4 (PRDX4) is one of a newly discovered family of antioxidative proteins. We generated human PRDX4 (hPRDX4) transgenic (Tg) mice, displaying a high level of hPRDX4 expression in the pancreatic islets, and then focused on the functions of PRDX4 in a type 1 diabetes mellitus (T1DM) model using a single high dose of streptozotocin (SHDS). After SHDS-injection, Tg mice showed significantly less hyperglycemia and hypoinsulinemia and a much faster response on glucose tolerance test than wild-type (WT) mice. Morphologic and immunohistochemical observation revealed that the pancreatic islet areas of Tg mice were larger along with less CD3-positive lymphocyte infiltration compared with WT mice. Upon comparison between these two mouse models, β-cell apoptosis was also repressed, and reversely, β-cell proliferation was enhanced in Tg mice. Real-time RT-PCR demonstrated that the expression of many inflammatory-related molecules and their receptors and transcription factors were significantly downregulated in Tg mice. These data indicate that PRDX4 can protect pancreatic islet β-cells against injury caused by SHDS-induced insulitis, which strongly suggests that oxidative stress plays an essential role in SHDS-induced diabetes. This study, for the first time, implicates that PRDX4 has a pivotal protective function against diabetes progression in this T1DM model.
Antioxidants & Redox Signaling 05/2010; 13(10):1477-90. · 8.20 Impact Factor
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ABSTRACT: We report a case of pulmonary capillary hemangiomatosis in a patient with aortic stenosis. An 86-year-old Japanese female with chronic heart failure due to aortic stenosis suddenly died during hemodialysis. At an autopsy, severe aortic stenosis and cardiomegaly with both left and right ventricular hypertrophy were noted. In the lung, a diffuse proliferation of capillaries in the thickened alveolar septum and collections of hemosiderin-laden macrophages in the alveolar space were observed. These indicated that long-standing passive congestion from aortic stenosis might result in the occurrence of pulmonary capillary hemangiomatosis.
Journal of UOEH 12/2009; 31(4):339-44.
