Plasminogen promotes cholesterol efflux by the ABCA1 pathway

Nathalie Pamir, Patrick M. Hutchins, Graziella E. Ronsein, Hao Wei, Chongren Tang, Riku Das, Tomas Vaisar, Edward Plow, Volker Schuster, Marlys L. Koschinsky, Catherine A. Reardon, Richard Weinberg, David A. Dichek, Santica Marcovina, Godfrey S. Getz, Jay W. Heinecke

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number15
DOIs
StatePublished - Aug 3 2017
Externally publishedYes

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Plasminogen
Apolipoproteins E
Cholesterol
Lipoprotein(a)
Macrophages
Cardiovascular Diseases
Apolipoprotein A-I
Ion Exchange Chromatography
Firearms
Proteomics
Gel Chromatography
Molecular Biology
Atherosclerosis
Proteins

Keywords

  • Atherosclerosis
  • Cholesterol
  • Endocrinology
  • Lipoproteins
  • Metabolism

Cite this

Pamir, N., Hutchins, P. M., Ronsein, G. E., Wei, H., Tang, C., Das, R., ... Heinecke, J. W. (2017). Plasminogen promotes cholesterol efflux by the ABCA1 pathway. JCI insight, 2(15). https://doi.org/10.1172/jci.insight.92176

Plasminogen promotes cholesterol efflux by the ABCA1 pathway. / Pamir, Nathalie; Hutchins, Patrick M.; Ronsein, Graziella E.; Wei, Hao; Tang, Chongren; Das, Riku; Vaisar, Tomas; Plow, Edward; Schuster, Volker; Koschinsky, Marlys L.; Reardon, Catherine A.; Weinberg, Richard; Dichek, David A.; Marcovina, Santica; Getz, Godfrey S.; Heinecke, Jay W.

In: JCI insight, Vol. 2, No. 15, 03.08.2017.

Research output: Contribution to journalArticle

Pamir, N, Hutchins, PM, Ronsein, GE, Wei, H, Tang, C, Das, R, Vaisar, T, Plow, E, Schuster, V, Koschinsky, ML, Reardon, CA, Weinberg, R, Dichek, DA, Marcovina, S, Getz, GS & Heinecke, JW 2017, 'Plasminogen promotes cholesterol efflux by the ABCA1 pathway', JCI insight, vol. 2, no. 15. https://doi.org/10.1172/jci.insight.92176
Pamir, Nathalie ; Hutchins, Patrick M. ; Ronsein, Graziella E. ; Wei, Hao ; Tang, Chongren ; Das, Riku ; Vaisar, Tomas ; Plow, Edward ; Schuster, Volker ; Koschinsky, Marlys L. ; Reardon, Catherine A. ; Weinberg, Richard ; Dichek, David A. ; Marcovina, Santica ; Getz, Godfrey S. ; Heinecke, Jay W. / Plasminogen promotes cholesterol efflux by the ABCA1 pathway. In: JCI insight. 2017 ; Vol. 2, No. 15.
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AU - Pamir, Nathalie

AU - Hutchins, Patrick M.

AU - Ronsein, Graziella E.

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AU - Tang, Chongren

AU - Das, Riku

AU - Vaisar, Tomas

AU - Plow, Edward

AU - Schuster, Volker

AU - Koschinsky, Marlys L.

AU - Reardon, Catherine A.

AU - Weinberg, Richard

AU - Dichek, David A.

AU - Marcovina, Santica

AU - Getz, Godfrey S.

AU - Heinecke, Jay W.

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AB - Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.

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