title: Vitamin K antagonism aggravates chronic kidney disease-induced neointimal hyperplasia and calcification in arterialized veins: role of vitamin K treatment?
abstract: Arteriovenous fistula (AVF) is the common vascular access type for a hemodialysis patient. Its failure is due to neointimal hyperplasia. Vitamin K antagonists are given to lower thrombosis tendency, but have side effects that enhance arterial calcifications. Here, we investigated the effects of vitamin K antagonists and vitamin K2 (K2) treatment on neointimal hyperplasia development and calcification in rats and in arterialized human veins. AVF was generated in female rats while chronic kidney disease (CKD) was induced using an adenine-enriched diet. Arterialization, CKD, and vitamin K antagonists all significantly enhanced venous neointimal hyperplasia. K2 treatment, additional to vitamin K antagonists, significantly reduced neointimal hyperplasia in arterialized veins in healthy rats but not in rats with CKD. Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD. K2 significantly enhanced matrix Gla protein carboxylation in control rats and rats with CKD. Arterialized human vein samples contained inactive matrix Gla protein at calcification and neointimal hyperplasia sites, indicating local vitamin K deficiency. Thus, vitamin K antagonists have detrimental effects on AVF remodeling, whereas K2 reduced neointimal hyperplasia and calcification indicating vasoprotective effects. Hence, K2 administration may be useful to prevent neointimal hyperplasia and calcification in arterialized veins
authors.forename: Emma
authors.initials: E
authors.lastname: Zaragatski
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Stephan
authors.initials: S
authors.lastname: Langer
authors.forename: Lieven
authors.initials: L
authors.lastname: Kennes
authors.forename: Miriam
authors.initials: M
authors.lastname: Tamm
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Koeppel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kranz
authors.forename: Tina
authors.initials: T
authors.lastname: Hackhofer
authors.forename: Karen
authors.initials: K
authors.lastname: Arakelyan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jacobs
authors.forename: Maria
authors.initials: M
authors.lastname: Kokozidou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D005268:Femoral Vein / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged; D058426:Neointima; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061205:Vascular Calcification / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D066253:Vascular Remodeling / Q000187:drug effects*; D014812:Vitamin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024482:Vitamin K 2 / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D024482:Vitamin K 2; D014812:Vitamin K