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


RESULTS
AGE-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.


CONCLUSIONS
Subcutaneous 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.
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. lovezhulin1982@163.com.|457th hospital of PLA, Wuhan, People's Republic of China. lovezhulin1982@163.com.
Lin
L
Zhu
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. dragonhzq@hotmail.com.
Zhiqing
Z
He
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. wufeng@163.com.|Department of Research, Center for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA. wufeng@163.com.
Feng
F
Wu
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. drdr1@163.com.
Ru
R
Ding
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. jiangqx@gmail.com.
Qixia
Q
Jiang
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. zhangjy@medmail.com.cn.
Jiayou
J
Zhang
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. fanm@medmail.com.cn.
Min
M
Fan
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. wangx@hotmail.com.
Xing
X
Wang
Experimental Cardiovascular Research, CRC 91:12, Lund University, Entrance 72, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden. Eva.Bengtsson@uadm.uu.se.
Bengtsson
B
Eva
Experimental Cardiovascular Research, CRC 91:12, Lund University, Entrance 72, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden. Eva.Bengtsson@uadm.uu.se.
Nilsson
N
Jan
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. chunliangliang@hotmail.com.
Chun
C
Liang
Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, 200003, People's Republic of China. wu_zonggui@yeah.net.
Zonggui
Z
Wu
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000175:diagnosis / Q000276:immunology*; D001323:Autoantibodies; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D017127:Glycation End Products, Advanced / Q000276:immunology / Q000378:metabolism*; D006943:Hyperglycemia / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism; D000093844:Glycated Proteins
D001057:Apolipoproteins E; D001323:Autoantibodies; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C099252:oxidized low density lipoprotein