Aim: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. Results: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4 +/+ /apoE -/ -). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE -/ -mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4 +/+ /apoE -/ -mice than in apoE -/ -mice. Bone marrow transplantation from hPRDX4 +/+ donors to apoE -/ -mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. Innovation: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE -/ -mice fed a high-cholesterol diet. Conclusion: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. Antioxid. Redox Signal. 17, 1362-1375.
Abstract-To clarify the role of histamine-producing cells and its origin in atherosclerosis, we investigated histidine decarboxylase (HDC; histamine-producing enzyme) expression in murine arteries with vascular injuries after the animal had received transplanted bone marrow (BM) from green fluorescent protein (GFP)-transgenic mice. The neointima in the ligated carotid arteries contained BM-derived HDC ϩ cells that expressed macrophage (Mac-3) or smooth muscle cell antigen (␣-SMA). In contrast, the HDC ϩ BM-derived cells, which were positive for Mac-3, were mainly located in the adventitia in the cuff replacement model. In apolipoprotein E-knockout mice on a high cholesterol diet, BM-derived cells expressing Mac-3 in the atheromatous plaques were also positive for HDC. In comparison with wild-type mice, HDC Ϫ/Ϫ mice showed reduced neointimal thickening and a decreased intima-to-media ratio after ligation and cuff replacement. These results indicate that histamine produced from BM-derived progenitor cells, which could transdifferentiate into SMC-or macrophage-like cells, are important for the formation of neointima and atheromatous plaques. Key Words: histamine Ⅲ histidine decarboxylase Ⅲ progenitor cells Ⅲ bone marrow Ⅲ vascular injury H istidine decarboxylase (HDC) is a rate-limiting enzyme for the production of histamine from L-histidine. Histamine plays an important role in allergy, inflammation, neurotransmission, and gastrointestinal functions by acting via specific histamine receptors. 1,2 With regards to the atherosclerotic coronary artery, histamine is a vasoconstrictor, and the accumulation of activated mast cells in the adventitia and ruptured plaques in acute coronary syndrome has been reported. [3][4][5] Another histamine-producing cell in the atherosclerotic lesion is the macrophage, 6 which is present in all stages of atherosclerosis and is a major cellular constituent of atheromatous plaques. Previously, we demonstrated that HDC is expressed in CD68 ϩ foam cells (macrophages) of human atherosclerotic lesions. 6 In monocytic human U937 cells, the expression of HDC and histamine H1 receptor (HH1R) is induced during macrophage differentiation, 6,7 and granulocyte macrophage-colony stimulating factor, one of the proinflammatory and macrophage-differentiation factors produced in the atherosclerotic lesions, 8 is also able to induce HDC and HH1R. 9 As a longer-term effect, histamine stimulates cultured human intimal smooth muscle cells (SMCs) to proliferate and to express matrix metalloproteinase-1 (MMP-1). 10 Histamine also upregulates the gene expression of endothelial nitric oxide synthase (eNOS) in vascular endothelial cells (ECs). 11 These histamine effects are all mediated via HH1R, which is expressed in the ECs, foam cells, and SMCs of human atherosclerotic lesions. 12 In the case of monocytes, we have reported that histamine upregulates lipopolysaccharideinduced expression of tumor necrosis factor-␣ (TNF-␣) during macrophage differentiation and switching of the histamine receptor from histamine H...
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.
Objective-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. Methods and Results-We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1 Ϫ/Ϫ / apoE Ϫ/Ϫ ) and analyzed atherosclerosis in ASK1 Ϫ/Ϫ /apoE Ϫ/Ϫ mice fed a high-cholesterol diet for 12 weeks. ASK1Ϫ/Ϫ /apoE Ϫ/Ϫ 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 Ϫ/Ϫ mice. Bone marrow transplantation from ASK1 Ϫ/Ϫ or wild-type to apoE Ϫ/Ϫ mice confirmed the above observation that the recipient mice of ASK1 Ϫ/Ϫ donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors. Conclusion-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.
Objective-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. Methods and Results-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-B, 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. Conclusion-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 hyperlipidemiainduced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:800-807.)Key Words: histamine Ⅲ histidine decarboxylase Ⅲ hyperlipidemia-induced atherosclerosis Ⅲ inflammation Ⅲ matrix metalloproteinase R ecently, evidence has emerged concerning inflammatory mechanisms of the initiation and progression of atherosclerosis. 1,2 Histamine, one of the classical inflammatory mediators, is synthesized from L-histidine by a rate-limiting enzyme, histidine decarboxylase (HDC). Histamine is released from mast cells and mediates type I hypersensitivity via histamine receptor H1 (HH1R), 3 and histamine produced by enterochromaffin-like cells induces gastric acid secretion from parietal cells via histamine receptor H2 (HH2R). 4 In the field of cardiovascular pathology, accumulation of activated mast cells and histamine in the coronary adventitia has been implicated in progression of plaque rupture and acute coronary syndrome. [5][6][7] In addition, several epidemiological studies have reported an enhancement of atherosclerosis in the patients of allergy or increased blood histamine. 8 -10 Together, these suggest a possible involvement of histamine in the pathogenesis of atherosclerosis and related disorders.Previously, we demonstrated that HDC-knockout (KO) mice showed reduced neointimal formation induced by ligation of the carotid artery or cuff replacement of the femoral artery. 11 Because histamine stimulates smooth muscle cells (SMCs) to proliferate and SMCs predominantly express HH1R, 12 the...
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