Immunization with advanced glycation end products modified low density lipoprotein inhibits atherosclerosis progression in diabetic apoE and LDLR null mice

Lin Zhu,Ru Ding,Qixia Jiang,Jiayou Zhang,Bengtsson Eva,Xing Wang,Zhiqing He,Nilsson Jan,Feng Wu,Zonggui Wu,Chun Liang,Min Fan

doi:10.1186/s12933-014-0151-6

Abstract

BackgroundDiabetes accelerates atherosclerosis through undefined molecular mechanisms. Hyperglycemia induces formation of advanced glycation end product (AGE)-modified low-density lipoprotein (LDL). Anti-AGE-LDL autoantibodies favor atherosclerosis (AS) progression in humans, while anti oxidized LDL immunization inhibits AS in hypercholesterolemic, non-diabetic mice. We here investigated if AGE-LDL immunization protects against AS in diabetic mice.MethodsAfter diabetes induction with streptozotocin and high fat diet, both low density lipoprotein receptor (LDLR)−/− and apoE female mice were randomized to: AGE-LDL immunization with aluminum hydroxide (Alum) adjuvant; Alum alone; or PBS.ResultsAGE-LDL immunization: significantly reduced AS; induced specific plasma IgM and IgG antibodies; upregulated splenic Th2, Treg and IL-10 levels, without altering Th1 or Th17 cells; and increased serum high density lipoprotein(HDL) while numerically lowering HbA1c levels.ConclusionsSubcutaneous immunization with AGE-LDL significantly inhibits atherosclerosis progression in hyperlipidemic diabetic mice possibly through activation of specific humoral and cell mediated immune responses and metabolic control improvement.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-014-0151-6) contains supplementary material, which is available to authorized users.

Highlights

Diabetes mellitus through as yet undefined mechanisms worsens short and long term clinical prognosis of cardiovascular disease (CVD) manifested as asymptomatic ischemic events and increased morbidity and mortality [1]
Characterization of Advanced glycation end product -modified low-density lipoprotein (AGE-low-density lipoprotein (LDL)) Because in vivo glycation of LDL is very complex involving nonenzymatic reaction of glucose and its metabolites with the free amino groups of lysine [35], native LDL (nLDL) and oxLDL were used as reference to characterize the AGELDL used as immunization agent
Immunization with Advanced glycation end products (AGEs)-LDL inhibits atherosclerosis in murine diabetic models Immunization with AGE-LDL using Aluminum hydroxide (Alum) as adjuvant resulted in a significant reduction in atherosclerotic lesion burden compared to mice immunized with phosphate-buffered saline (PBS) control (76% in low density lipoprotein receptor (LDLR) null diabetes mellitus(DM) mice, p < 0.01; and 43% in apoE null Diabetes mellitus (DM) mice, p < 0.01) or Alum alone (50% in LDLR null DM mice, p < 0.05; and 20% in apoE null DM mice, p < 0.05) (Figure 1)

Summary

Introduction

Diabetes mellitus through as yet undefined mechanisms worsens short and long term clinical prognosis of cardiovascular disease (CVD) manifested as asymptomatic ischemic events and increased morbidity and mortality [1]. No current therapy targets diabetesinduced CVD, promising immunization strategies against AS have been developed [2,3,4,5,6,7,8,9], supported by: association between autoantibodies against oxidized plasma low density lipoprotein (ox-LDL) and AS in. Diabetes accelerates atherosclerosis through undefined molecular mechanisms. Hyperglycemia induces formation of advanced glycation end product (AGE)-modified low-density lipoprotein (LDL). Anti-AGE-LDL autoantibodies favor atherosclerosis (AS) progression in humans, while anti oxidized LDL immunization inhibits AS in hypercholesterolemic, non-diabetic mice. We here investigated if AGE-LDL immunization protects against AS in diabetic mice

Methods

Results

Conclusion