title: Correction of endothelial dysfunction after selective homocysteine lowering gene therapy reduces arterial thrombogenicity but has no effect on atherogenesis.
abstract: Hyperhomocysteinemia is an independent risk factor for ischemic cardiovascular diseases, but its causal role in atherothrombosis remains controversial. Proatherogenic and/or prothrombotic effects may underlie the potential causal relation between hyperhomocysteinemia and cardiovascular events. Here, the effects of selective lowering of plasma homocysteine, plasma cholesterol, or both on endothelial function and on atherogenesis in male hyperlipidemic and hyperhomocysteinemic C57BL/6 low-density lipoprotein receptor (LDLr)(-/-)/cystathionine-β-synthase (CBS)(+/-)-deficient mice were investigated. Second, we evaluated whether selective homocysteine lowering has anti-thrombotic effects in a model of arterial thrombosis. A hyperhomocysteinemic and atherogenic diet was started at the age of 12 weeks. Three weeks later, gene transfer was performed with E1E3E4-deleted adenoviral vectors for hepatocyte-restricted overexpression of CBS (AdCBS) or of the LDLr (AdLDLr), or with the control vector Adnull. In a fourth group, AdCBS and AdLDLr were co-administered. Selective homocysteine lowering but not selective cholesterol lowering restored endothelial function at 6 weeks after gene transfer. Intimal area in the aortic root and in the brachiocephalic artery at 13 weeks was more than 100-fold (p < 0.001) smaller in AdLDLr and AdCBS/AdLDLr mice than in control mice and AdCBS mice. No differences in intimal area were observed between control mice and AdCBS mice. In a model of carotid artery thrombosis, the average time to first occlusion and to stable occlusion were 1.9-fold (p < 0.01) and 2.1-fold longer (p < 0.01), respectively, in AdCBS-treated mice than in control mice. Taken together, these data show that correction of endothelial dysfunction following selective homocysteine lowering has anti-thrombotic but no anti-atherogenic effects.
authors.affiliation: Center for Molecular and Vascular Biology, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobs
authors.forename: Eline
authors.initials: E
authors.lastname: Van Craeyveld
authors.forename: Ilayaraja
authors.initials: I
authors.lastname: Muthuramu
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Gordts
authors.forename: Jan
authors.initials: J
authors.lastname: Emmerechts
authors.forename: Marc
authors.initials: M
authors.lastname: Hoylaerts
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D050197:Atherosclerosis / Q000150:complications / Q000503:physiopathology* / Q000628:therapy*; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008076:Cholesterol, HDL / Q000097:blood; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006710:Homocysteine / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism / Q000627:therapeutic use; D013927:Thrombosis / Q000150:complications / Q000503:physiopathology* / Q000628:therapy; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D008076:Cholesterol, HDL; D011973:Receptors, LDL; D006710:Homocysteine; D003541:Cystathionine beta-Synthase; D000109:Acetylcholine