Jian-Feng Wu1, Yan Wang2, Min Zhang3, Yan-Yan Tang3, Bo Wang4, Ping-Ping He3, Yun-Cheng Lv3, Xin-Ping Ouyang3, Feng Yao3, Yu-Lin Tan3, Shi-Lin Tang5, Deng-Pei Tang6, Francisco S Cayabyab7, Xi-Long Zheng8, Da-Wei Zhang9, Gao-Feng Zeng10, Chao-Ke Tang11. 1. 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. 2. 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. 3. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China. 4. Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China. 5. Department of Intensive Care Unit, The First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China. 6. Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7H 5E5, Canada. 7. Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan S7H 5E5, Canada. 8. 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. 9. Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. 10. Department of Cardiovascular Medicine, The Second Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China. Electronic address: qichingnudou@tom.com. 11. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang 421001, Hunan, China. Electronic address: tangchaoke@qq.com.
Abstract
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. METHODS AND 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. CONCLUSION: 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.
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. METHODS AND 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. CONCLUSION: 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.
Authors: Maryam Barma; Faisel Khan; Rosemary J G Price; Peter T Donnan; C Martina Messow; Ian Ford; Alex McConnachie; Allan D Struthers; Marion E T McMurdo; Miles D Witham Journal: Aging Clin Exp Res Date: 2016-10-12 Impact factor: 3.636
Authors: Judith J De Haan; Saskia Haitjema; Hester M den Ruijter; Gerard Pasterkamp; Gert J de Borst; Martin Teraa; Marianne C Verhaar; Hendrik Gremmels; Saskia C A de Jager Journal: J Am Heart Assoc Date: 2017-08-30 Impact factor: 5.501