An auxiliary factor of mammalian multi-aminoacyltRNA synthetases, p43, is thought to be a precursor of endothelial monocyte-activating polypeptide II (EMAP II) that triggers proinflammation in leukocytes and macrophages. In the present work, however, we have shown that p43 itself is specifically secreted from intact mammalian cells, while EMAP II is released only when the cells are disrupted. Secretion of p43 was also observed when its expression was increased. These results suggest that p43 itself should be a real cytokine secreted by an active mechanism. To determine the cytokine activity and active domain of p43, we investigated tumor necrosis factor (TNF) and interleukin-8 (IL-8) production from human monocytic THP-1 cells treated with various p43 deletion mutants. The full length of p43 showed higher cytokine activity than EMAP II, further supporting p43 as the active cytokine. p43 was also shown to activate MAPKs and NFB, and to induce cytokines and chemokines such as TNF, IL-8, MCP-1, MIP-1␣, MIP-1␤, MIP-2␣, IL-1␤, and RANTES. Interestingly, the high level of p43 was observed in the foam cells of atherosclerotic lesions. Therefore, p43 could be a novel mediator of atherosclerosis development as well as other inflammation-related diseases.

Abstract:The maintenance of balance between nitric oxide (NO) and the superoxide anion is required for proper functioning of the endothelium. To investigate the relationship between genetic factors associated with endothelial function and the development of coronary artery disease (CAD), endothelial nitric oxide synthase (ecNOS) gene a/b polymorphism and NADH/NADPH oxidase p22 phox gene C242T polymorphism were examined in 305 Korean male CAD patients and 215 healthy male control subjects. The ␤-fibrinogen gene H1/H2 polymorphism was also analyzed. Both ecNOS a/b and p22 phox C242T polymorphisms were found to be associated with the development of CAD in the study population (p = 0.020 and 0.011, respectively). When the association was analyzed by age, statistical significance was retained only in those Ͻ51 years (p = 0.021 and 0.025 for the a/b and the C242T polymorphism, respectively) and not in those Ͼ51 years of age (p =0.155 and 0.278 respectively). However, the distribution of the ␤-fibrinogen H1/H2 genotypes was not found to be associated with the development of CAD in either the Յ50 (p = 0.611) or Ͼ50 groups (p = 0.188). The ecNOS gene a/b polymorphism and the NADH/NADPH oxidase p22 phox gene C242T polymorphism were found to be significantly associated with the development of CAD in Korean male patients less than 51 years old.

BackgroundInflammation and activation of immune cells have important roles in the pathogenesis of atherosclerosis. We analyzed the involvement of various immune cells in the pathogenesis of atherosclerosis.MethodsWe investigated the presence of foam cells, lymphocytes and killer cells in 11 atherosclerotic plaque specimens removed from Korean patients who underwent carotid endoarterectomy. Atherosclerotic plaques were analyzed by immunohistochemistry using monoclonal antibody specific to foam cells (anti-CD68), pan-T cells (anti-CD3), helper-T cells (anti-CD4), cytotoxic T cells (anti-CD8), granular component of killer cells (anti-TIA-1) and pan-B cells (anti-CD20).ResultsAnalysis revealed a general infiltration of immune cells not only in atherosclerotic plaques but also in the vascular wall adjacent to the plaque. Heavy infiltration of CD68+ macrophage was observed in all cases. In addition, significant infiltration of CD3+ T-lymphocytes was observed in all cases, while CD20+ B-cells were observed in only a few cases. Majority of the CD3+ cells was found to be CD4+ helper-T cells. CD8+ cytotoxic T cells and TIA-1+ cells were less prominent.ConclusionAnalysis of the human atherosclerotic plaques suggested that helper-T cells and foam cells had a major role in the plaque development.

Background and Objectives Inflammation and activation of immune cells play important roles in the pathogenesis of atherosclerosis. We investigated the activation status of plasma inflammatory markers and immune cells in angina patients. Methods We analyzed the plasma level of C-reactive protein CRP as a marker of inflammation in 24 patients with angina pectoris 12 unstable angina, 12 stable angina , and 12 normal subjects. The degree of activation of peripheral blood monocytes was assessed by Northern analysis of pro-atherogenic cytokines and the activation status of T-lymphocytes was measured by flow-cytometric analysis of HLA-DR expression on T-cells. Results Plasma level of CRP was highest in unstable angina patients 1.63 0.70 mg/l and lowest in the control subjects 0.22 0.08 mg/l p 0.03 . We also observed a high correlation between CRP level and the occurrence of minor and major coronary events during 6 months of follow-up. The percentage of HLA-DR positive T-lymphocyte was significantly increased in the unstable angina patients 26.8 1.4% compared with that in the control 14.7 1.2% p 0.0053 . When baseline levels of cytokine mRNA were measured in monocytes, the percentages of the patients expressing higher than normal levels of IL-8, IL-1b, MCP-1, and TF mRNAs was 37.5, 29.2, 33.3, and 37.5%, respectively p 0.0143, 0.0371, 0.0233, and 0.0143, respectively . Basal mRNA levels of interleukin IL -8, tissue factor TF , IL-1b and monocyte chemoattractant protein-1 MCP-1 showed a strong correlation with each other

Background and Objectives：Recent reports have demonstrated that perturbation of the balance between myosin light chain (MLC) phosphorylation and the dephosphorylation status is associated with the development of cardiac hypertrophy. Myosin light chain phosphatase (MLCP) is a key enzyme that regulates the phosphorylation status of the MLC, but its functional roles in cardiac muscle have not been well investigated. Especially, the functions of the small-subunit of MLCP in cardiac muscles are not well elucidated. Here, whether the human heart-specific small-subunit (M21) of MLCP is associated with hypertrophic responses in a transgenic mice model were assessed. Materials and Methods：The transgenic mice, overexpressing the human M21, were generated from a cardiac-specific transgenic construct. Cardiac tissues from the transgenic mice were subjected to histology for their morphological examination. The echocardiographic parameters of the murine heart were examined with transgenic mice aged 1, 2 and 3 months, and compared with their non-transgenic littermates. To determine whether the transgenic heart was sensitive to stress, the echocardiographic examination was also performed at the baseline, both before and after the administration of isoproterenol, at a dosage of 30 μg/g/day, for 2 weeks. Results： The histological analysis of the transgenic heart revealed myocyte disarray and nuclear hypertrophy. No significant differences were observed between the transgenic and non-transgenic mice in relation to the echocardiographic determinants, such as the left ventricular dimensions and the wall thickness. Chronic cardiac stress, induced by isoproterenol infusion, also failed to show any significant differences in relation to the same determinants. Conclusion： Overexpression of the human M21 in the murine heart induced myocyte hypertrophy. However, the overall cardiac functions were not affected under normal and stressed conditions.

Background and ObjectiveThe aging process affects the responsiveness and other functions of endothelium and vascular smooth muscle cells, predisposing the old vessels to the development of atherosclerotic lesions. Endothelial nitric oxide synthase ecNOS gene polymorphism was shown to affect the occurrence of acute myocardial infarction AMI . We hypothesized that aging may affect the association between the ecNOS gene polymorphism and AMI. Methods We investigated the age-related distribution of the ecNOS gene a/b polymorphism in 121 male AMI patients and 206 age-matched healthy male controls. As a control, we also genotyped b-fibrinogen gene H1/H2 polymorphism in the same population. Results The aa, ab, and bb genotypes were found in 1, 49 and 156 cases among the control subjects and 5, 23 and 93 cases among the AMI patients, respectively. There was a significant association between the ecNOS polymorphism and AMI p 0.045 . When the correlation was analyzed by age, the significance remained only in the group below the age of 51 p 0.009 . The distribution of the b-fibrinogen gene H1/H2 alleles, however, was not found to be associated with development of AMI in both young p 0.7400 and old p 0.2160 population. Conclusion Our results provide the first evidence that links ecNOS polymorphism to the risk of AMI in relation to age. Young persons who smoke or have ecNOS aa genotype may have an increased risk of developing AMI. The functional as well as structural changes associated with aging in the vascular endothelium may mask the effect of the ecNOS polymorphism in the development of AMI in old people.