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.

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

“…These investigators have also recently demonstrated that HO-1 upregulation by adenoassociated viral gene delivery improved AVF blood flow and reduced AVF venous wall thickness (19). Moreover, this group has also demonstrated that HO-2 plays an important role in maintaining AVF blood flow and function in murine AVF models (16). Second, MCP-1, an inflammatory mediator, which regulates chemotaxis of monocytes and macrophages, activation of endothelial cells, and proliferation of smooth muscle cells, plays a critical role in AVF dysfunction (17).…”

Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo

“…These experiments primarily used 10-to 12-wk-old male C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME). These experiments also used age-and sex-matched HO-1 Ϫ/Ϫ mice, HO-2 Ϫ/Ϫ mice, and their respective control mice generated from relevant colonies maintained as we have previously described (20,30,44). HO-1 ϩ/ϩ and HO-1 Ϫ/Ϫ mice were in the age range of 20 to 35 wk, and HO-2 ϩ/ϩ and HO-2 Ϫ/Ϫ mice were in the age range of 10 to 50 wk.…”

“…While the induction of HO-1 is often viewed as a cytoprotective response, all products resulting from HO-based degradation of heme are potentially toxic, and, indeed, injurious effects have been ascribed to induced HO-1 (23,27,50). The other HO isoform, constitutively expressed HO-2, is also of interest in tissue injury since, depending on the experimental setting, protective or injurious effects may emanate from HO-2 (30,42,53).…”

Future research directions to improve fistula maturation and reduce access failure

“…In murine AVF, HO-1 gene expression is markedly induced in the vascular smooth muscle cells; HO-1 knockout mice how reduced patency with thinner vein walls and increased luminal area, as well as increased expression of proinflammatory and pro-oxidant mediators such as MCP-1, MMP-2 and MMP-9 [139]. A functional AVF also requires HO-2 [135]. Shear stress can regulate HO-1 activity, with high flow inducing HO-1 to generate NO and mitochondria-derived hydrogen peroxide; low flow induces lower levels of HO-1 that lead to macrophage infiltration and superoxide production within the vessel wall, suggesting an important role for HO in promoting outward remodeling and preventing NIH [140].…”