PMID- 23118130
OWN - NLM
STAT- MEDLINE
DCOM- 20130802
LR  - 20220310
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Linking)
VI  - 97
IP  - 2
DP  - 2013 Feb 1
TI  - CTLA4-IgG ameliorates homocysteine-accelerated atherosclerosis by inhibiting 
      T-cell overactivation in apoE(-/-) mice.
PG  - 349-59
LID - 10.1093/cvr/cvs330 [doi]
AB  - AIMS: Cytotoxic T lymphocyte antigen 4 (CTLA4) exerts inhibitory effects on 
      T-cell activation by competition with CD28. In this study, we investigated the 
      effect of CTLA4-IgG on homocysteine (Hcy)-induced T-cell activation and potential 
      signal pathways involved in atherosclerotic formation. METHODS AND RESULTS: The 
      CD28 signal was significantly amplified by Hcy treatment in splenic T cells and 
      hyperhomocysteinaemia (HHcy)-accelerated plaques in apolipoprotein E-deficient 
      (apoE(-/-)) mice. As a major competitor of CD28, CTLA4-IgG (abatacept) 
      pretreatment, 100 mug/week, in apoE(-/-) mice could reverse 2- and 4-week 
      HHcy-accelerated atherosclerosis. Furthermore, the membrane level of CTLA4 was 
      decreased and the endocytosis level was increased by HHcy. Endocytosed CTLA4 
      molecules by Hcy were in large vesicles, colocalized with lysosomes and 
      endosomes. Hcy-increased CTLA4 endocytosis and secretion of inflammatory 
      cytokines in T cells were blocked by CTLA4-IgG and the PI3K inhibitor LY294002. 
      Blocking the CD28 signal pathway in T cells significantly decreased Hcy-promoted 
      macrophage migration. CONCLUSION: These results illustrate a novel mechanism of 
      CD28-dependent T-cell costimulation involved in HHcy-accelerated atherosclerosis, 
      which extends the pharmacological application of CTLA4-IgG for atherosclerosis.
FAU - Ma, Kongyang
AU  - Ma K
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Science, 
      Peking University, Beijing 100191, PR China.
FAU - Lv, Silin
AU  - Lv S
FAU - Liu, Bo
AU  - Liu B
FAU - Liu, Ziyi
AU  - Liu Z
FAU - Luo, Yuhong
AU  - Luo Y
FAU - Kong, Wei
AU  - Kong W
FAU - Xu, Qingbo
AU  - Xu Q
FAU - Feng, Juan
AU  - Feng J
FAU - Wang, Xian
AU  - Wang X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121031
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Apolipoproteins E)
RN  - 0 (CD28 Antigens)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Ctla4 protein, mouse)
RN  - 0 (Immunoconjugates)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-2)
RN  - 7D0YB67S97 (Abatacept)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Abatacept
MH  - Animals
MH  - Apolipoproteins E/physiology
MH  - Atherosclerosis/*drug therapy/etiology
MH  - CD28 Antigens/metabolism
MH  - CTLA-4 Antigen/metabolism
MH  - Endocytosis
MH  - Female
MH  - Hyperhomocysteinemia/*complications
MH  - Immunoconjugates/*therapeutic use
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Interferon-gamma/biosynthesis
MH  - Interleukin-2/biosynthesis
MH  - Lymphocyte Activation/drug effects
MH  - Macrophages/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - T-Lymphocytes/*drug effects/immunology
EDAT- 2012/11/03 06:00
MHDA- 2013/08/03 06:00
CRDT- 2012/11/03 06:00
PHST- 2012/11/03 06:00 [entrez]
PHST- 2012/11/03 06:00 [pubmed]
PHST- 2013/08/03 06:00 [medline]
AID - cvs330 [pii]
AID - 10.1093/cvr/cvs330 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2013 Feb 1;97(2):349-59. doi: 10.1093/cvr/cvs330. Epub 2012 Oct 
      31.