title: Hepatocyte-specific Dyrk1a gene transfer rescues plasma apolipoprotein A-I levels and aortic Akt/GSK3 pathways in hyperhomocysteinemic mice.
abstract: Hyperhomocysteinemia, characterized by high plasma homocysteine levels, is recognized as an independent risk factor for cardiovascular diseases. The increased synthesis of homocysteine, a product of methionine metabolism involving B vitamins, and its slower intracellular utilization cause increased flux into the blood. Plasma homocysteine level is an important reflection of hepatic methionine metabolism and the rate of processes modified by B vitamins as well as different enzyme activity. Lowering homocysteine might offer therapeutic benefits. However, approximately 50% of hyperhomocysteinemic patients due to cystathionine-beta-synthase deficiency are biochemically responsive to pharmacological doses of B vitamins. Therefore, effective treatments to reduce homocysteine levels are needed, and gene therapy could provide a novel approach. We recently showed that hepatic expression of DYRK1A, a serine/threonine kinase, is negatively correlated with plasma homocysteine levels in cystathionine-beta-synthase deficient mice, a mouse model of hyperhomocysteinemia. Therefore, Dyrk1a is a good candidate for gene therapy to normalize homocysteine levels. We then used an adenoviral construct designed to restrict expression of DYRK1A to hepatocytes, and found decreased plasma homocysteine levels after hepatocyte-specific Dyrk1a gene transfer in hyperhomocysteinemic mice. The elevation of pyridoxal phosphate was consistent with the increase in cystathionine-beta-synthase activity. Commensurate with the decreased plasma homocysteine levels, targeted hepatic expression of DYRK1A resulted in elevated plasma paraoxonase-1 activity and apolipoprotein A-I levels, and rescued the Akt/GSK3 signaling pathways in aorta of mice, which can prevent homocysteine-induced endothelial dysfunction. These results demonstrate that hepatocyte-restricted Dyrk1a gene transfer can offer a useful therapeutic targets for the development of new selective homocysteine lowering therapy.
authors: Univ Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptative Biology, EAC-CNRS 4413, 75013 Paris, France.
authors: Asma
authors: A
authors: Tlili
authors: Frank
authors: F
authors: Jacobs
authors: Leanne
authors: L
authors: de Koning
authors: Sirine
authors: S
authors: Mohamed
authors: Linh-Chi
authors: LC
authors: Bui
authors: Julien
authors: J
authors: Dairou
authors: Nicole
authors: N
authors: Belin
authors: Véronique
authors: V
authors: Ducros
authors: Thierry
authors: T
authors: Dubois
authors: Jean-Louis
authors: JL
authors: Paul
authors: Jean-Maurice
authors: JM
authors: Delabar
authors: Bart
authors: B
authors: De Geest
authors: Nathalie
authors: N
authors: Janel
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood*; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D022781:Hepatocytes / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000235:genetics / Q000628:therapy; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014161:Transduction, Genetic; D000097603:Dyrk Kinases
chemical_list: D016632:Apolipoprotein A-I; D003541:Cystathionine beta-Synthase; D006710:Homocysteine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000097603:Dyrk Kinases