Your browser doesn't support javascript.
loading
Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice.
Modder, Melanie; Het Panhuis, Wietse In; Li, Mohan; Afkir, Salwa; Dorn, Alexandra L; Pronk, Amanda C M; Streefland, Trea C M; Lalai, Reshma A; Pierrou, Stefan; Nilsson, Stefan K; Olivecrona, Gunilla; Kooijman, Sander; Rensen, Patrick C N; Schönke, Milena.
Afiliación
  • Modder M; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Het Panhuis WI; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Li M; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Afkir S; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Dorn AL; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Pronk ACM; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Streefland TCM; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Lalai RA; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Pierrou S; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Nilsson SK; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Olivecrona G; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Kooijman S; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Rensen PCN; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
  • Schönke M; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Cardiovasc Res ; 2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39259836
ABSTRACT
BACKGROUND AND

AIMS:

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid uptake from triglyceride-rich lipoproteins such as VLDL. While pharmacological inhibition of ANGPTL3 is being evaluated as lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aimed to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. METHODS AND

RESULTS:

Mice were subcutaneously injected twice-weekly with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides.Liver-targeted Angptl4 silencing reduced plasma triglycerides (-48%) and total cholesterol (-56%), explained by higher VLDL-derived fatty acid uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma triglycerides in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma triglycerides independent of nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects.

CONCLUSIONS:

Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well-tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido