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Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia.
Kockx, Maaike; Glaros, Elias; Leung, Betty; Ng, Theodore W; Berbée, Jimmy F P; Deswaerte, Virginie; Nawara, Diana; Quinn, Carmel; Rye, Kerry-Anne; Jessup, Wendy; Rensen, Patrick C N; Meikle, Peter J; Kritharides, Leonard.
Afiliação
  • Kockx M; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Glaros E; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Leung B; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Ng TW; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Berbée JF; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Deswaerte V; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Nawara D; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Quinn C; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Rye KA; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Jessup W; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Rensen PC; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Meikle PJ; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
  • Kritharides L; From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart a
Arterioscler Thromb Vasc Biol ; 36(7): 1338-49, 2016 07.
Article em En | MEDLINE | ID: mdl-27150391
ABSTRACT

OBJECTIVE:

Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)). APPROACH AND

RESULTS:

Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9.

CONCLUSIONS:

We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de LDL / Ciclosporina / Metabolismo dos Lipídeos / Hiperlipidemias Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Assunto da revista: ANGIOLOGIA Ano de publicação: 2016 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de LDL / Ciclosporina / Metabolismo dos Lipídeos / Hiperlipidemias Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Assunto da revista: ANGIOLOGIA Ano de publicação: 2016 Tipo de documento: Article