title: Functioning of an arteriovenous fistula requires heme oxygenase-2.
abstract: Heme oxygenase-2 (HO-2), the constitutive isoform of the heme-degrading enzyme heme oxygenase, may serve as an anti-inflammatory vasorelaxant, in part, by generating carbon monoxide. Arteriovenous fistulas (AVFs) are employed as hemodialysis vascular accesses because they provide an accessible, high-blood-flow vascular segment. We examined the role of vascular expression of HO-2 in AVF function. An AVF was created in mice by anastomosing the carotid artery to the jugular vein. HO-2 expression was detected by immunohistochemistry in the intact carotid artery, mainly in endothelial cells and smooth muscle cells; expression of HO-2 protein and mRNA was modestly increased in the artery of the AVF. Creating an AVF in HO-2(-/-) mice compared with an AVF in HO-2(+/+) mice led to markedly reduced AVF blood flow and increased numbers of nonfunctioning AVFs. The impairment of AVF function in the setting of HO-2 deficiency could not be ascribed to either preexisting intrinsic abnormalities in endothelium-dependent and endothelium-independent relaxation of the carotid artery in HO-2-deficient mice or to impaired vasorelaxant responses in the intact carotid artery in vivo. HO-1 mRNA was comparably induced in the AVF in HO-2(+/+) and HO-2(-/-) mice, whereas the AVF in HO-2(-/-) mice compared with that in HO-2(+/+) mice exhibited exaggerated induction of matrix metalloproteinase (MMP)-9 but similar induction of MMP-2. HO-2 deficiency also led to lower AVF blood flow when AVFs were created in uremia, the latter induced by subtotal nephrectomy. We conclude that HO-2 critically contributes to the adequacy of AVF blood flow and function.
authors.affiliation: Mayo Clinic, Guggenheim 542, 200 First St. SW, Rochester, MN 55905. nath.karl@mayo.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Kang
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
mesh_terms: D000818:Animals; D001164:Arteriovenous Fistula / Q000378:metabolism* / Q000503:physiopathology; D002339:Carotid Arteries / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007150:Immunohistochemistry; D007601:Jugular Veins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*
chemical_list: D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2
keywords: arteriovenous fistula; heme oxygenase-2; hemodialysis; vascular access