Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCζ/SP1 pathway in THP-1 macrophages.
OBJECTIVE
The aim of this study was to determine whether ATP-binding cassette transporter A1 (ABCA1) was up-regulated by growth differentiation factor-15 (GDF-15) via the phosphoinositide 3-kinase (PI3K)/protein kinase Cζ (PKCζ)/specificity protein 1 (SP1) pathway in THP-1 macrophages.


RESULTS
We investigated the effects of different concentrations of GDF-15 on ABCA1 expression in THP-1 macrophages. The results showed that GDF-15 dramatically increased cholesterol efflux and decreased cellular cholesterol levels. In addition, GDF15 increased ABCA1 mRNA and protein levels. The effects of GDF-15 on ABCA1 protein expression and cellular cholesterol efflux were abolished by wither inhibition or depletion of PI3K, PKCζ and SP1, respectively, suggesting the potential roles of PI3K, PKCζ and SP1 in ABCA1 expression. Taken together, GDF-15 appears to activate PI3K, PKCζ and SP1 cascade, and then increase ABCA1 expression, thereby promoting cholesterol efflux and reducing foam cell formation.


CONCLUSIONS
Our results suggest that GDF-15 has an overall protective effect on the progression of atherosclerosis, likely through inducing ABCA1 expression via the PI3K/PKCζ/SP1 signaling pathway and enhancing cholesterol efflux.
Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China; Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Jian-Feng
JF
Wu
Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China; Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China.
Yan
Y
Wang
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Min
M
Zhang
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Yan-Yan
YY
Tang
Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China.
Bo
B
Wang
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Ping-Ping
PP
He
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Yun-Cheng
YC
Lv
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Xin-Ping
XP
Ouyang
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Feng
F
Yao
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China.
Yu-Lin
YL
Tan
Department of Intensive Care Unit, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China.
Shi-Lin
SL
Tang
Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7H 5E5, Canada.
Deng-Pei
DP
Tang
Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan S7H 5E5, Canada.
Francisco S
FS
Cayabyab
Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada.
Xi-Long
XL
Zheng
Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Da-Wei
DW
Zhang
Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China. Electronic address: qichingnudou@tom.com.
Gao-Feng
GF
Zeng
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China. Electronic address: tangchaoke@qq.com.
Chao-Ke
CK
Tang
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D055436:Growth Differentiation Factor 15; D058539:Phosphatidylinositol 3-Kinase; D011493:Protein Kinase C; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D000099221:Protein Kinase C zeta; C577836:ABCA1 protein, human
ABCA1; Atherosclerosis; Cholesterol efflux; GDF-15