Newly identified antiatherosclerotic activity of methotrexate and adalimumab: Complementary effects on lipoprotein function and macrophage cholesterol metabolism

Nicoletta Ronda, Daniela Greco, Maria Pia Adorni, Francesca Zimetti, Elda Favari, Gunnbjørg Hjeltnes, Knut Mikkelsen, Maria Orietta Borghi, Ennio Giulio Favalli, Rita Gatti, Ivana Hollan, Pier Luigi Meroni, Franco Bernini

Research output: Contribution to journalArticle

Abstract

Objective Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti-tumor necrosis factor α agents in RA is considered secondary to their anti-inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high-density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol-loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling. Methods Sera from RA patients treated with MTX (n=34) or with adalimumab and MTX (n=22) obtained before treatment, after 6 weeks of treatment, and after 6 months of treatment were analyzed for CEC and CLC by radioisotopic and fluorometric techniques, respectively. The influence of MTX and adalimumab on macrophage cholesterol efflux and uptake was evaluated in vitro using human THP-1-derived macrophages. Results MTX treatment was associated with increases in serum HDL, low-density lipoprotein, and total cholesterol levels and with ATP-binding cassette G1-mediated and scavenger receptor class B type I (SR-BI)-mediated increases in CEC; MTX treatment was not associated with modifications in CLC. Adalimumab treatment was associated with increases in serum HDL levels, a transient increase in SR-BI-mediated CEC, a transient decrease in ATP-binding cassette A1-mediated CEC, and a significant reduction in CLC; in addition, adalimumab reduced macrophage cholesterol uptake in vitro. Conclusion Antiatherosclerotic activity asso-ciated with MTX and adalimumab may be mediated by beneficial and complementary effects on lipoprotein functions and on macrophage cholesterol handling. As a whole, these mechanisms may oppose foam cell formation.

Original languageEnglish
Pages (from-to)1155-1164
Number of pages10
JournalArthritis and Rheumatology
Volume67
Issue number5
DOIs
Publication statusPublished - May 1 2015

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Methotrexate
Lipoproteins
Macrophages
Cholesterol
Rheumatoid Arthritis
Foam Cells
HDL Lipoproteins
Serum
CD36 Antigens
Adalimumab
Therapeutics
Adenosine Triphosphate
LDL Cholesterol
Atherosclerosis
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Medicine(all)

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Newly identified antiatherosclerotic activity of methotrexate and adalimumab : Complementary effects on lipoprotein function and macrophage cholesterol metabolism. / Ronda, Nicoletta; Greco, Daniela; Adorni, Maria Pia; Zimetti, Francesca; Favari, Elda; Hjeltnes, Gunnbjørg; Mikkelsen, Knut; Borghi, Maria Orietta; Favalli, Ennio Giulio; Gatti, Rita; Hollan, Ivana; Meroni, Pier Luigi; Bernini, Franco.

In: Arthritis and Rheumatology, Vol. 67, No. 5, 01.05.2015, p. 1155-1164.

Research output: Contribution to journalArticle

Ronda, N, Greco, D, Adorni, MP, Zimetti, F, Favari, E, Hjeltnes, G, Mikkelsen, K, Borghi, MO, Favalli, EG, Gatti, R, Hollan, I, Meroni, PL & Bernini, F 2015, 'Newly identified antiatherosclerotic activity of methotrexate and adalimumab: Complementary effects on lipoprotein function and macrophage cholesterol metabolism', Arthritis and Rheumatology, vol. 67, no. 5, pp. 1155-1164. https://doi.org/10.1002/art.39039
Ronda, Nicoletta ; Greco, Daniela ; Adorni, Maria Pia ; Zimetti, Francesca ; Favari, Elda ; Hjeltnes, Gunnbjørg ; Mikkelsen, Knut ; Borghi, Maria Orietta ; Favalli, Ennio Giulio ; Gatti, Rita ; Hollan, Ivana ; Meroni, Pier Luigi ; Bernini, Franco. / Newly identified antiatherosclerotic activity of methotrexate and adalimumab : Complementary effects on lipoprotein function and macrophage cholesterol metabolism. In: Arthritis and Rheumatology. 2015 ; Vol. 67, No. 5. pp. 1155-1164.
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abstract = "Objective Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti-tumor necrosis factor α agents in RA is considered secondary to their anti-inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high-density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol-loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling. Methods Sera from RA patients treated with MTX (n=34) or with adalimumab and MTX (n=22) obtained before treatment, after 6 weeks of treatment, and after 6 months of treatment were analyzed for CEC and CLC by radioisotopic and fluorometric techniques, respectively. The influence of MTX and adalimumab on macrophage cholesterol efflux and uptake was evaluated in vitro using human THP-1-derived macrophages. Results MTX treatment was associated with increases in serum HDL, low-density lipoprotein, and total cholesterol levels and with ATP-binding cassette G1-mediated and scavenger receptor class B type I (SR-BI)-mediated increases in CEC; MTX treatment was not associated with modifications in CLC. Adalimumab treatment was associated with increases in serum HDL levels, a transient increase in SR-BI-mediated CEC, a transient decrease in ATP-binding cassette A1-mediated CEC, and a significant reduction in CLC; in addition, adalimumab reduced macrophage cholesterol uptake in vitro. Conclusion Antiatherosclerotic activity asso-ciated with MTX and adalimumab may be mediated by beneficial and complementary effects on lipoprotein functions and on macrophage cholesterol handling. As a whole, these mechanisms may oppose foam cell formation.",
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T2 - Complementary effects on lipoprotein function and macrophage cholesterol metabolism

AU - Ronda, Nicoletta

AU - Greco, Daniela

AU - Adorni, Maria Pia

AU - Zimetti, Francesca

AU - Favari, Elda

AU - Hjeltnes, Gunnbjørg

AU - Mikkelsen, Knut

AU - Borghi, Maria Orietta

AU - Favalli, Ennio Giulio

AU - Gatti, Rita

AU - Hollan, Ivana

AU - Meroni, Pier Luigi

AU - Bernini, Franco

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N2 - Objective Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti-tumor necrosis factor α agents in RA is considered secondary to their anti-inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high-density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol-loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling. Methods Sera from RA patients treated with MTX (n=34) or with adalimumab and MTX (n=22) obtained before treatment, after 6 weeks of treatment, and after 6 months of treatment were analyzed for CEC and CLC by radioisotopic and fluorometric techniques, respectively. The influence of MTX and adalimumab on macrophage cholesterol efflux and uptake was evaluated in vitro using human THP-1-derived macrophages. Results MTX treatment was associated with increases in serum HDL, low-density lipoprotein, and total cholesterol levels and with ATP-binding cassette G1-mediated and scavenger receptor class B type I (SR-BI)-mediated increases in CEC; MTX treatment was not associated with modifications in CLC. Adalimumab treatment was associated with increases in serum HDL levels, a transient increase in SR-BI-mediated CEC, a transient decrease in ATP-binding cassette A1-mediated CEC, and a significant reduction in CLC; in addition, adalimumab reduced macrophage cholesterol uptake in vitro. Conclusion Antiatherosclerotic activity asso-ciated with MTX and adalimumab may be mediated by beneficial and complementary effects on lipoprotein functions and on macrophage cholesterol handling. As a whole, these mechanisms may oppose foam cell formation.

AB - Objective Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti-tumor necrosis factor α agents in RA is considered secondary to their anti-inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high-density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol-loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling. Methods Sera from RA patients treated with MTX (n=34) or with adalimumab and MTX (n=22) obtained before treatment, after 6 weeks of treatment, and after 6 months of treatment were analyzed for CEC and CLC by radioisotopic and fluorometric techniques, respectively. The influence of MTX and adalimumab on macrophage cholesterol efflux and uptake was evaluated in vitro using human THP-1-derived macrophages. Results MTX treatment was associated with increases in serum HDL, low-density lipoprotein, and total cholesterol levels and with ATP-binding cassette G1-mediated and scavenger receptor class B type I (SR-BI)-mediated increases in CEC; MTX treatment was not associated with modifications in CLC. Adalimumab treatment was associated with increases in serum HDL levels, a transient increase in SR-BI-mediated CEC, a transient decrease in ATP-binding cassette A1-mediated CEC, and a significant reduction in CLC; in addition, adalimumab reduced macrophage cholesterol uptake in vitro. Conclusion Antiatherosclerotic activity asso-ciated with MTX and adalimumab may be mediated by beneficial and complementary effects on lipoprotein functions and on macrophage cholesterol handling. As a whole, these mechanisms may oppose foam cell formation.

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