title: Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor.
abstract: Macrophage migration inhibitory factor (MIF) involves the pathogenesis of atherosclerosis (AS) and increased plasma MIF levels in diabetes mellitus (DM) patients are associated with AS. Here, we have been suggested that MIF could be a critical contributor for the pathological process of diabetes-associated AS by using adenovirus-mediated RNA interference. First, streptozotocin (STZ)-induced diabetic animal model was constructed in 114 apolipoprotein E-deficient mice (apoE-/- mice) fed on a regular chow diet. Then, the animals were randomly divided into three groups: Adenovirus-mediated MIF interference (Ad-MIFi), Ad-enhanced green fluorescent protein (EGFP) and normal saline (NS) group (n ≈ 33/group). Non-diabetic apoE-/- mice (n = 35) were served as controls. Ad-MIFi, Ad-EGFP and NS were, respectively, injected into the tail vein of mice from Ad-MIFi, Ad-EGFP and NS group, which were injected repeatedly 4 weeks later. Physical, biochemical, morphological and molecular parameters were measured. The results showed that diabetic apoE-/- mice had significantly aggravated atherosclerotic lesions. MIF gene interference attenuated atherosclerotic lesions and stabilized atheromatous plaque, accompanied by the decreased macrophages and lipids deposition and inflammatory cytokines production, improved glucose intolerance and plasma cholesterol level, the decreased ratio of matrix matalloproteinase-2/tissue inhibitor of metalloproteinase-1 and plaque instability index. An increased expression of MIF and its ligand CD74 was also detected in the diabetic patients with coronary artery disease. The results suggest that MIF gene interference is able to inhibit atherosclerotic lesions and increase plaque stability in diabetic apoE-/-mice. MIF inhibition could be a novel and promising approach to the treatment of DM-associated AS.
authors: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Shandong University Qilu Hospital, Jinan, Shandong, China.
authors: Hui
authors: H
authors: Sun
authors: XianJun
authors: X
authors: Zhang
authors: Lei
authors: L
authors: Zhao
authors: Xi
authors: X
authors: Zhen
authors: ShanYing
authors: S
authors: Huang
authors: ShaSha
authors: S
authors: Wang
authors: Hong
authors: H
authors: He
authors: ZiMo
authors: Z
authors: Liu
authors: NaNa
authors: N
authors: Xu
authors: FaLin
authors: F
authors: Yang
authors: ZhongHua
authors: Z
authors: Qu
authors: ZhiYong
authors: Z
authors: Ma
authors: Cheng
authors: C
authors: Zhang
authors: Yun
authors: Y
authors: Zhang
authors: Qin
authors: Q
authors: Hu
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000071518:Liver X Receptors; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D001057:Apolipoproteins E; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D008263:Macrophage Migration-Inhibitory Factors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; C045084:invariant chain; D002784:Cholesterol; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: apolipoprotein E-deficient mice; atherosclerosis; diabetes mellitus; inflammation; macrophage migration inhibitory factor