Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor.

Hui Sun,Lei Zhao,Falin Yang,Hong He,Qin Hu,Xianjun Zhang,Yun Zhang,Zhiyong Ma,Zhonghua Qu,Zimo Liu,Shasha Wang,Shanying Huang,Cheng Zhang,Xi Zhen,Nana Xu

doi:10.1111/jcmm.12521

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.

Highlights

Diabetes mellitus (DM) is a systemic disease affecting both the quality and length of life
Adenovirus-mediated MIF interference (Ad-MIFi) or Ad-enhanced green fluorescent protein (EGFP) diluted to a total volume of 100 ll was, respectively, injected into the tail vein of each mouse in two intervention DM groups, while the mice injected with normal saline served as vehicle controls
As a ligand of migration inhibitory factor (MIF), CD74 protein and mRNA level was significantly upregulated after STZ-induced hyperglycaemia, as detected by the

Summary

Introduction

Diabetes mellitus (DM) is a systemic disease affecting both the quality and length of life. It is well-established that atherosclerosis is a major complication of both type 1 and type 2 DM [1, 2]. 75% of patients diagnosed with diabetes died from atherosclerosis-related cardiovascular diseases such as myocardial infarction (MI), peripheral artery disease and stroke [3, 4]. DM patient with coronary artery disease (CAD) has become a major public health concern [5]. The mechanisms whereby diabetes accelerates cardiovascular disease are still unclear. Recent studies have identified that atherosclerosis with DM has low-grade inflammation which can stimulate macrophage-foam cell formation [6, 7]

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Results

Conclusion