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Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients.
Ministrini, Stefano; Niederberger, Rebecca; Akhmedov, Alexander; Beer, Georgia; Puspitasari, Yustina M; Franzini, Maria; Vergaro, Giuseppe; Cannie, Douglas E; Elliott, Perry; Kahr, Peter C; Hock, Christoph; Kobza, Richard; Toggweiler, Stefan; Lüscher, Thomas F; Camici, Giovanni G; Stämpfli, Simon F.
Afiliação
  • Ministrini S; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
  • Niederberger R; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
  • Akhmedov A; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
  • Beer G; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
  • Puspitasari YM; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
  • Franzini M; Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
  • Vergaro G; Cardiology Division, Fondazione Toscana Gabriele Monasterio, Via Giuseppe Moruzzi 1, 56126 Pisa, Italy.
  • Cannie DE; Institute of Cardiovascular Science, University College London, 62 Huntley St, Wc1E 6Dd London, UK; Barts Heart Center, St. Bartholomew's Hospital, West Smithfield, Ec1A 7Be London, UK.
  • Elliott P; Institute of Cardiovascular Science, University College London, 62 Huntley St, Wc1E 6Dd London, UK; Barts Heart Center, St. Bartholomew's Hospital, West Smithfield, Ec1A 7Be London, UK.
  • Kahr PC; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Neurimmune, Wagistrasse 18, 8952 Schlieren, Switzerland.
  • Hock C; Neurimmune, Wagistrasse 18, 8952 Schlieren, Switzerland; Institute for Regenerative Medicine (IREM), Wagistrasse 12, 8952 Schlieren, Switzerland.
  • Kobza R; Cardiology Division, Heart Center, Luzerner Kantonsspital, Spitalstrasse 16, 6000 Lucerne, Switzerland.
  • Toggweiler S; Cardiology Division, Heart Center, Luzerner Kantonsspital, Spitalstrasse 16, 6000 Lucerne, Switzerland.
  • Lüscher TF; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Royal Brompton and Harefield Hospitals and Imperial College, London, UK.
  • Camici GG; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Department of Research and Education, University Hospital Zurich, Rämistrasse 100, 8092 Zurich, Switzerland.
  • Stämpfli SF; Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Cardiology Division, Heart Center, Luzerner Kantonsspital, Spitalstrasse 16, 6000 Lucerne, Switzerland. Electronic address: simon.staempfli@luks.ch.
Vascul Pharmacol ; 156: 107411, 2024 Sep.
Article em En | MEDLINE | ID: mdl-39029855
ABSTRACT

INTRODUCTION:

Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect.

METHODS:

Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction.

RESULTS:

Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 activator colivelin partially rescued the expression of TF.

CONCLUSIONS:

Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzoxazóis / Tromboplastina / Fator de Necrose Tumoral alfa / Neuropatias Amiloides Familiares / Células Endoteliais / Fator de Transcrição STAT3 / Cardiomiopatias Idioma: En Revista: Vascul Pharmacol Assunto da revista: ANGIOLOGIA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Suíça País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzoxazóis / Tromboplastina / Fator de Necrose Tumoral alfa / Neuropatias Amiloides Familiares / Células Endoteliais / Fator de Transcrição STAT3 / Cardiomiopatias Idioma: En Revista: Vascul Pharmacol Assunto da revista: ANGIOLOGIA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Suíça País de publicação: Estados Unidos