Objective-Interleukin (IL)-1 plays an important role in atherosclerosis. IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1. However, the role of IL-1Ra in the development of atherosclerosis is poorly understood. Methods and Results-Mice that lacked IL-1Ra (IL-1RaϪ/Ϫ) were crossed with apolipoprotein E-deficient (EϪ/Ϫ) mice and formation of atherosclerotic lesions was analyzed after 16 weeks or 32 weeks consumption of a normal chow diet. This study focused on the comparison of atherosclerotic lesion between IL-1Raϩ/ϩ/apoEϪ/Ϫ (nϭ12) and IL-1Ra/apoEϪ/Ϫ mice (nϭ12), because of the significantly leaner phenotype in IL-1RaϪ/Ϫ/apoEϪ/Ϫ mice compared with the others. Interestingly, atherosclerotic lesion size in IL-1Raϩ/Ϫ/apoEϪ/Ϫ mice at age 16 weeks was significantly increased (30%) compared with IL-1Raϩ/ϩ/apoEϪ/Ϫ mice (PϽ0.05). At 32 weeks, the differences of lesion size between these mice failed to achieve statistical significance. However, immunostaining demonstrated an 86% (PϽ0.0001) increase in the MOMA-2-stained lesion area of IL-1Raϩ/Ϫ/apoEϪ/Ϫ mice. In addition, ␣-actin staining in these lesions was significantly decreased (Ϫ15%) compared with those in IL-1Raϩ/ϩ/apoEϪ/Ϫ mice (PϽ0.05). Conclusions-These

Background-The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease.Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood. Methods and Results-Using IL-1Ra-deficient (IL-1RaϪ/Ϫ ; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra ϩ/ϩ ) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. nterleukin (IL)-1 is a proinflammatory cytokine thought to play an important role in inflammation and atherosclerosis. 1,2 Activity of this interleukin is counterregulated by its endogenous inhibitor IL-1 receptor antagonist (IL-1Ra). 1-2 A recent study investigating expression of IL-1 and IL-1Ra transcripts in the vascular wall after mechanistic insult suggested the possibility that IL-1Ra may attenuate the biological function of IL-1␤ in this setting. 3 However, direct evidence implicating endogenous IL-1Ra in neointimal formation remained yet to be provided. The present study definitively tested the hypothesis that IL-1Ra deficiency promotes intimal hyperplasia after arterial injury by using IL-1Ra-deficient mice. Methods Animals IL-1Ra-deficient (IL-1RaϪ/Ϫ ) mice were generated in our laboratory by replacing the exons encoding the secreted form with the neo gene, as previously described. 4 Embryonic stem cells were aggregated with 2 (C57BL/6J ϫ DBA/2)F1 mice at the 8-cell stage. In these mutant mice, all 4 isoforms of the IL-1Ra were destroyed. These mice were backcrossed to C57BL/6J strain mice for 8 generations. Next, heterozygous mice were intercrossed with each other to obtain homozygous mutant mice. The studies were carried out according to the protocols approved by the National Defense Medical College Board for Studies in Experimental Animals. Femoral Artery InjuryMice (8 weeks of age) were anesthetized by intraperitoneal injection of pentobarbital (50 mg/kg), and the left femoral artery was dissected from its surroundings, as described previously. 5 Vascular injury was inflicted by placing a nonocclusive polyethylene cuff (length 2 mm; internal diameter 0.56 mm; Becton Dickinson) around the femoral artery. Tissue Preparation and HistologySubsequent to tail-cuff systolic blood pressure measurement, the animals were euthanized by pentobarbital injection and the vascular tree perfused with 0.9% NaCl followed by 4% paraformaldehyde. After perfusion, the femoral artery was harvested, fixed overnight in 4% paraformaldehyde, embedded in OCT compounds (Tissue-Tek; Sakura Finetechnical Co, Tokyo, Japan), and sectioned (10- MorphometryTen equally spaced cross sections were used in all mice to quantify intimal lesions. The luminal circumference, the circumference of internal elastic lamina, and the circumference of external elastic lamina were measured by using the NIH Image 1.55 ...

However, the precise role of interleukin-1 (IL-1), one of the major proinflammatory cytokines, in the myocardium is not fully understood. In this study, we investigated the pathophysiological consequences of cardiac expression of IL-1 in vivo. We generated mice with a cardiac-specific overexpression of human IL-1␣. We then analyzed their heart morphology and functions. Histological and echocardiographic analyses revealed concentric LV hypertrophy with preserved LV systolic function in the mice. Our results suggest that myocardial expression of IL-1 is sufficient to cause LV hypertrophy. myocardium; left ventricular systolic function; cardiovascular disease INTERLEUKIN-1 (IL-1), one of the proinflammatory cytokines, exerts a wide variety of effects, such as an immune response, cell proliferation, and cell death, on many different cell types (4). An elevated expression of IL-1 in hearts has been revealed in a variety of cardiovascular diseases, including myocarditis (22), myocardial infarction (18), and congestive heart failure (13,18,22). IL-1 is also highly expressed in the hypertrophied myocardium in vitro and in vivo (21).We previously reported that mice with a ubiquitous overexpression of human IL-1␣ (hIL-1␣), which were originally generated as a mouse model of rheumatoid arthritis, unexpectedly showed prominent left ventricular (LV) hypertrophy (7). The study did not, however, define whether the specific expression of IL-1␣ in the myocardium caused the LV hypertrophy, because the systemic expressions might induce the LV hypertrophy. Therefore, to elucidate the role of myocardial expression of IL-1␣ in the myocardium, we developed transgenic (Tg) mice with a constitutive overexpression of hIL-1␣ restricted to cardiomyocytes under the control of ␣-myosin heavy chain (MHC) promoter.The Tg mice exhibited concentric LV hypertrophy with a preserved LV systolic function. Our data suggest that cardiac expression of IL-1 thus is sufficient to cause LV hypertrophy. METHODS

Aim: Tumor necrosis factor receptor 1 (TNFR1) participates importantly in arterial inflammation in genetically altered mice; however it remains undetermined whether a selective TNFR1 antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist in the suppression of arterial inflammation.