The tumor necrosis factor receptor superfamily (TNFRSF), which includes CD40, LIGHT, and OX40, plays important roles in the initiation and progression of cardiovascular diseases, involving atherosclerosis. CD137, a member of TNFRSF, is a well-known activation-induced T cell co-stimulatory molecule and has been reported to be expressed in human atherosclerotic plaque lesions, and plays pivotal roles in mediating disease processes. In this review, we focus on and summarize recent advances in mouse studies on the involvement of CD137 signaling in the pathogenesis and plaque stability of atherosclerosis, thereby highlighting a valuable therapeutic target in atherosclerosis.
Animals ; Atherosclerosis* ; Cardiovascular Diseases ; Humans ; Mice ; Negotiating ; Plaque, Atherosclerotic ; Receptors, Tumor Necrosis Factor

Autophagy is a life-sustaining process by which cytoplasmic constituents are segregated in double-lipid bilayer membrane vesicles and undergo degradation into lysosomes. In recent studies, the basal autophagy is an indispensable process mediating proper vascular function in the body. Moreover, autophagy activated by many stress-related stimuli in the arterial wall protects endothelial cells and smooth muscle cells against cell death and the progression of vascular disease including atherosclerosis. Autophagy is protective to atherosclerosis during early stage but becomes dysfunctional in advanced atherosclerotic lesions. Following this finding, the need is emphasized which pharmacological development with compounds that activate the protective effects of autophagy in the vascular disease. Autophagy stimulated by oral or vascular delivery of rapamycin or derivatives effectively suppressed the atherosclerotic plaque growth and plaque destabilization. In this review, the recent finding is summarized on the role of autophagy in atherosclerosis and find out whether the activation or rescue of autophagy could provide a breakthrough in the treatment of atherosclerosis.
Atherosclerosis* ; Autophagy* ; Cell Death ; Cytoplasm ; Endothelial Cells ; Lysosomes ; Membranes ; Myocytes, Smooth Muscle ; Negotiating ; Plaque, Atherosclerotic ; Sirolimus ; Vascular Diseases

Deregulation of G1 cyclins has been reported in several human and rodent tumors including colon cancer. To investigate the expression pattern of G1 cyclins in 1,2- dimethyl-hydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis, we studied the expression of cyclin D1 and cyclin E by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry (IHC). The mRNA level of cyclin D1 was increased 1.2-fold in adenocarcinomas but not significantly in adenomas, when compared with normal rat colonic mucosa (p<0.05). The cyclin E mRNA level was increased 2.7-fold in adenomas and 3.3-fold in adenocarcinomas (p<0.05). The PCNA mRNA level was also increased 1.9-fold in adenomas and 1.8-fold in adenocarcinomas (p<0.05). Immunohistochemical staining revealed exclusive nuclear staining of the neoplastic cells for cyclin D1, cyclin E and PCNA. Cyclin D1 expression was detected in 56.3% of the adenomas and in 61.5% of the adenocarcinomas examined, whereas cyclin E expression was detected in 87.5% of the adenomas and in 92.3% of the adenocarcinomas. Overall, cyclin D1, cyclin E and PCNA expression was significantly increased at both the mRNA and protein levels in normal colonic mucosa, adenomas and adenocarcinomas, but there was no significant difference in the degree of expression of these genes in adenomas and adenocarcinomas. Our results indicate that the overexpression of cyclin D1 and cyclin E may play an important role during the multistage process of rat colon carcinogenesis, at a relatively early stage, and may disturb cell-cycle control in benign adenomas, and thereafter, participate in tumor progression.
1,2-Dimethylhydrazine/toxicity ; Adenocarcinoma/*chemically induced/metabolism ; Adenoma/*chemically induced/metabolism ; Animals ; Carcinogens/toxicity ; Cell Cycle/drug effects/physiology ; Colon/metabolism ; Colonic Neoplasms/*chemically induced/metabolism ; Cyclin D1/*biosynthesis/genetics ; Cyclin E/*biosynthesis/genetics ; Gene Expression Regulation, Neoplastic ; Immunohistochemistry ; Male ; Proliferating Cell Nuclear Antigen/biosynthesis/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction

Diabetes is accompanied by delayed wound healing and insufficient granulation tissue formation, possibly because of a defect in fibroblast function. Maintaining glucose level at acceptable low level is considered to be an important part of the clinical treatment of diabetes, but the exact mechanism by which diabetes delays wound repair is not yet known. This study was designed to evaluate the effects of glucose on proliferation([3H]-thymidine uptake) and collagen synthesis([3H]-proline uptake) in dermal fibroblasts from non-lesional skins and chronic wounds. The subjects were divided into 3 groups: non-diabetic control(n = 5), glucose controlled(glycated Hb < 7%) diabetics(n = 5), and glucose uncontrolled(glycosylated Hb > 8%) diabetics(n = 5). The fibroblasts were cultured in two conditions, low glucose(5 mM) and high glucose(20 mM) medium. The data were compared using Mann-Whitney test. The results are as follows: 1. There were no significant differences in the proliferation and collagen synthesis of non-lesional skin fibroblasts in all groups. 2. In high glucose medium culture, the proliferation of the fibroblasts from the wound of the glucose uncontrolled diabetic group was significantly lower than those of the other 2 groups(p< 0.05), and the collagen synthesis of the wound fibroblasts of the control group was significantly higher than those of 2 diabetic groups(p< 0.05). 3. The proliferation and collagen synthesis of the wound fibroblasts in all groups were significantly lower than those of the non-lesional skin fibroblasts(p< 0.05). 4. In the control group and the glucose controlled diabetic group, the proliferation of the wound fibroblasts in the high glucose culture media were lower than those in the low glucose culture media(p< 0.05). Also, in the glucose controlled diabetic group, the collagen synthesis of the wound fibroblasts in the high glucose culture medium was lower than that in the low glucose culture medium(p< 0.05). These results demonstrate that the glucose level may affect the proliferation and collagen synthesis of fibroblasts, and the strict blood glucose control is beneficial to the prevention and treatment of diabetic chronic wounds.
Blood Glucose ; Collagen* ; Culture Media ; DNA* ; Fibroblasts* ; Glucose* ; Granulation Tissue ; Skin ; Wound Healing ; Wounds and Injuries*

Precise redox balance is essential for the optimum health and physiological function of the human body. Furthermore, an unbalanced redox state is widely believed to be part of numerous diseases, ultimately resulting in death. In this review, we discuss the relationship between redox balance and cardiovascular disease (CVD). In various animal models, excessive oxidative stress has been associated with increased atherosclerotic plaque formation, which is linked to the inflammation status of several cell types. However, various antioxidants can defend against reactive oxidative stress, which is associated with an increased risk of CVD and mortality. The different cardiovascular effects of these antioxidants are presumably due to alterations in the multiple pathways that have been mechanistically linked to accelerated atherosclerotic plaque formation, macrophage activation, and endothelial dysfunction in animal models of CVD, as well as in in vitro cell culture systems. Autophagy is a regulated cell survival mechanism that removes dysfunctional or damaged cellular organelles and recycles the nutrients for the generation of energy. Furthermore, in response to atherogenic stress, such as the generation of reactive oxygen species, oxidized lipids, and inflammatory signaling between cells, autophagy protects against plaque formation. In this review, we characterize the broad spectrum of oxidative stress that influences CVD, summarize the role of autophagy in the content of redox balance-associated pathways in atherosclerosis, and discuss potential therapeutic approaches to target CVD by stimulating autophagy.

Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis.
Atherosclerosis ; Autophagy ; Cholesterol* ; Foam Cells ; Homeostasis ; Hydrolysis ; Lipid Droplets ; Lysosomes ; Macrophages*

Background: Non-alcoholic fatty liver disease (NAFLD) has been increasing in association with the epidemic of obesity and diabetes. Peroxisomes are single membrane-enclosed organelles that play a role in the metabolism of lipid and reactive oxygen species. The present study examined the role of peroxisomes in high-fat diet (HFD)-induced NAFLD using fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist. Methods: Eight-week-old male C57BL/6J mice were fed either a normal diet or HFD for 12 weeks, and fenofibrate (50 mg/kg/day) was orally administered along with the initiation of HFD. Results: HFD-induced liver injury as measured by increased alanine aminotransferase, inflammation, oxidative stress, and lipid accumulation was effectively prevented by fenofibrate. Fenofibrate significantly increased the expression of peroxisomal genes and proteins involved in peroxisomal biogenesis and function. HFD-induced attenuation of peroxisomal fatty acid oxidation was also significantly restored by fenofibrate, demonstrating the functional significance of peroxisomal fatty acid oxidation. In Ppara deficient mice, fenofibrate failed to maintain peroxisomal biogenesis and function in HFD-induced liver injury. Conclusion The present data highlight the importance of PPARα-mediated peroxisomal fitness in the protective effect of fenofibrate against NAFLD.

Obesity and type 2 diabetes mellitus are world-wide health problems, and lack of understanding of their linking mechanism is one reason for limited treatment options. We determined if genetic deletion of vimentin, a type 3 intermediate filament, affects obesity and type 2 diabetes mellitus.

OBJECTIVES: Several reports demonstrated that ethanol administration impairs the DNA synthesis in rat hepatocytes. Also, it has been demonstrated that prostaglandin (PG) helps prevent membrane damage by hepatotoxic chemicals. In this study, the authors examined PG's effects on the toxicity of ethanol in the primary culture of rat regenerations. METHODS: We examined two kinds of parameters, i.e., DNA synthesis and lipid peroxidation in the primary culture of rat hepatocytes. Hepatocytes were isolated by the collagenase perfusion method. The rate of DNA synthesis was determined by pulse-labelling cultured cells with [3H]-thymidine. Incorporation of (3H)-thymidine was determined by liquid scintillation spectrophotometer. DNA content was measured by the fluorescence spectrophotometer. The lipid peroxidation was assayed with spectrophotometer. RESULTS: The results were as follows: 1) PG family (PGA1, PGD2, PGE1, PGE2, PGG2a, PGI2 & Thromboxane B2) stimulated the DNA synthesis of hepatocytes (especially PGD2 and PGE1), 2) ethanol decreased DNA synthesis by clear dose-dependent manner, 3) the combined treatment of PGD2 or PGE1, prevents the decreasing of DNA synthesis, which was induced by ethanol, 4) in ethanol treatment, lipid peroxidation was decreased significantly, but PGD2, PGE1 and PGA1 were not affected, and 5) PGD2, PGE1 and PGA1 decreased lipid peroxidation with ethanol, significantly. CONCLUSIONS: From these results, we concluded that PG could be useful for the treatment of degenerative liver disease and alcohol-induced liver disease in the assumption that further studies on the action mechanisms of PG will continue.
Animal ; Cells, Cultured ; DNA/biosynthesis ; Drug Interactions ; Ethanol/toxicity* ; Lipid Peroxidation/drug effects ; Liver/metabolism ; Liver/drug effects* ; Prostaglandins, Synthetic/pharmacology* ; Rats

KR-31543, (2S, 3R, 4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethyoxymethyl-3-hydroxy-2-methyl-2H-1-benz opyran is a new neuroprotective agent for ischemia-reperfusion damage. It has also been reported that KR-31543 has protective effects on lipid peroxidation and H2O2-induced reactive oxygen species production. In this study, we investigated the anti-inflammatory and anti-atherogenic properties of KR-31543. We observed that KR-31543 treatment reduced the production of MCP-1, IL-8, and VCAM-1 in HUVECs, and of MCP-1 and IL-6 in THP-1 human monocytes. We also examined the effect of KR-31543 on monocytes migration in vitro. KR-31543 treatment effectively reduced the migration of THP-1 human monocytes to the HUVEC monolayer in a dose-dependent manner. We next examined the effects of this compound on atherogenesis in LDL receptor deficient (Ldlr-/-) mice. After 10 weeks of western diet, the formation of atherosclerotic lesion in aorta was reduced in the KR-31543-treated group compared to the control group. The accumulation of macrophages in lesion was also reduced in KR-31543 treated group. However, the plasma levels of total cholesterol, HDL, LDL, and triglyceride were not affected by KR-31543 treatment. Taken together, these results show that KR-31543 has anti-inflammatory properties on human monocytes and endothelial cells, and inhibits fatty streak lesion formation in mouse model of atherosclerosis, suggesting the potential of KR-31543 for the treatment for atherosclerosis.
Animals ; Aorta/pathology ; Atherosclerosis/blood/*drug therapy/pathology ; Benzopyrans/*pharmacology/therapeutic use ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Diet ; Disease Models, Animal ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Inflammation Mediators/*metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Macrophages/metabolism ; Mice ; Mice, Transgenic ; Monocytes/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Receptors, CCR2/metabolism ; Receptors, LDL/genetics ; Tetrazoles/*pharmacology/therapeutic use ; Transendothelial and Transepithelial Migration/drug effects ; Triglycerides/blood ; Vascular Cell Adhesion Molecule-1/metabolism