Background and Purpose-Recent studies have shown that the cellular immune response in the development of vascular remodeling modulates the resulting pathological alterations. We show that hypoxia-inducible factor 1 (Hif-1) (specifically expressed in T cells) is involved in the immune response to vascular remodeling that accompanies arteriosclerosis. Methods and Results-To study the role of T cells in the development of vascular remodeling, femoral arterial injury induced by an external vascular polyethylene cuff was examined in mice lacking Hif-1 (specifically in T cells). We found that cuff placement caused prominent neointimal hyperplasia of the femoral artery in Hif-1-(T-cell)-deficient mice compared with that in control mice and that infiltration of inflammatory cells at the adventitia was markedly increased in the mutant mice. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice showed enhanced production of cytokines by activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice. T he vascular response to mechanical arterial injury involved in arteriosclerosis or in-stent restenosis leads to neointimal formation and inward remodeling. Recent studies have shown that the immune system plays an important role in the development of vascular remodeling in response to arterial injury. 1 Studies 2-4 in mice have shown that arterial injury is associated with local accumulation of antibodies, and mice lacking functional T and B cells exhibit increased neointima formation, indicating that adaptive immune responses to neoantigens in the damaged tissue modulate the vascular remodeling. During the development of vascular remodeling, a hypoxic microenvironment accompanying arteriosclerosis or stent-mediated overdistention in the injured vascular region is thought to be one of the factors modulating proliferation of myofibroblasts and increased matrix synthesis in the adventitial region. 5 It has also been reported that hypoxia accelerates the progression of atherosclerosis 6,7 and modulates vascular remodeling after arterial injury. 8 Several studies 10,11 have shown evidence of hypoxia within the arterial wall in atherosclerosis in an animal model 9 and in human disease. Adaptation to low oxygen tension in local tissues is important for activities of immune cells, because immune cells are often exposed to different oxygen tensions that markedly affect cellular metabolism as they survey different tissue microenvironments. 12 Hypoxia-inducible factor 1 (Hif-1) is a transcription factor that regulates gene expression in response to hypoxia; it is composed of heterodimers of an oxygensensitive ␣ subunit and a constitutively expressed ␤ subunit (also known as arylhydrocarbon receptor nuclear translocator). Hif-1␣ regulates the expressions of genes in response to hypoxia to maintain physiological oxygen homeostasis. 14 In addition to hypoxic stabilization of Hif-1␣, resulting in upregulation of Hif-1␣ functions, several factors relevant to infla...

Aim: Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent. However, anti-atherogenic effects of ezetimibe have not been fully elucidated. Therefore, the objective in this study was to clarify the vascular protective effects of ezetimibe in patients with hypercholesterolemia. Methods: Ezetimibe was administered to 20 patients with hypercholesterolemia (group E), and 20 age-and sex-matched patients with hypercholesterolemia were followed as controls (group C). Difference in metabolic profiles and cardiovascular surrogate markers before ezetimibe treatment and after 12 weeks of ezetimibe treatment were statistically evaluated. Results: Ezetimibe treatment significantly reduced serum levels of low-density lipoprotein cholesterol (LDL-C) and malondialdehyde-modified low-density lipoprotein (MDA-LDL). In addition, the values of body mass index, body weight, waist circumference, plasma HbA1c and urinary albumin were significantly decreased in group E compared to those in group C. On the other hand, high-density lipoprotein cholesterol (HDL-C) and adiponectin levels were significantly increased in group E compared to those in group C. The values of brachial-ankle pulse wave velocity (ba-PWV), mean arterial blood pressure (m-ABP), and % of flow-mediated dilation (FMD) were significantly improved in group E. Furthermore, ultrasonic studies demonstrated amelioration of the vascular stiffness of common carotid arteries in group E but not in group C. These vascular protective effects of ezetimibe were statistically correlated with the decreased values of MDA-LDL and MDA-LDL-to-LDL-C ratio but not with those of LDL-C. Conclusion: Ezetimibe has a lipid lowering-independent vascular protective effect in patients with hypercholesterolemia through decreasing oxidative stress.

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