ß-Catenin is markedly induced in a murine model of an arteriovenous fistula: the effect of metalloproteinase inhibition.
Neointimal hyperplasia contributes to failure of hemodialysis arteriovenous fistulas (AVFs). Increased expression of matrix metalloproteinase (MMP)-9 occurs in AVFs, and MMP-9 is implicated in neointimal hyperplasia and vascular injury. Recent studies demonstrate that MMP-9, by degrading N-cadherin, leads to increased expression of β-catenin and β-catenin-dependent proliferation of smooth muscle cells. The present study examined this pathway in the venous limb of a murine AVF model. Western analyses demonstrate that, in this model, there is diminished expression of N-cadherin accompanied by increased expression of β-catenin, c-Myc, and proliferating cell nuclear antigen (PCNA). By immunohistochemistry, β-catenin and c-Myc localized to proliferating smooth muscle cells in the venous limb of the AVF. Increased expression of β-catenin was accompanied by augmented expression of phosphorylated (p)-glycogen synthase kinase (GSK)-3β, GSK-3β, and integrin-linked kinase. The administration of doxycycline suppressed MMP-9 expression but did not reduce venous histological injury in the AVF, or increase AVF patency assessed 6 wk after its creation. Doxycycline did not influence expression of β-catenin, c-Myc, GSK-3β, or integrin-linked kinase. Thus, in this vascular injury model, the upregulation of β-catenin cannot be readily attributed to MMP-9 upregulation; increased β-catenin expression may reflect either the upregulation of p-GSK-3β, GSK-3β, or integrin-linked kinase. This study provides the first exploration of β-catenin in an AVF, demonstrating substantial upregulation of this mitogenic signaling molecule and uncovering possible mechanisms that may account for such upregulation.
Nath
Karl A
KA
Division of Nephrology and Hypertension, Department of Physiology and Biomedical Engineering, Mayo Clinic, Guggenheim 542, 200 First St., SW, Rochester, MN 55905, USA. nath.karl@mayo.edu
Grande
Joseph P
JP
Kang
Lu
L
Juncos
Julio P
JP
Ackerman
Allan W
AW
Croatt
Anthony J
AJ
Katusic
Zvonimir S
ZS
D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D015820:Cadherins / Q000096:biosynthesis; D002339:Carotid Arteries / Q000601:surgery; D004318:Doxycycline / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D006965:Hyperplasia / Q000517:prevention & control; D007601:Jugular Veins / Q000601:surgery; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D058426:Neointima / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D015854:Up-Regulation; D051176:beta Catenin / Q000096:biosynthesis*; D000099200:Scaffold Protein ILK
D015820:Cadherins; D004318:Doxycycline; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D061965:Matrix Metalloproteinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C489083:Cdh2 protein, mouse; C489428:Myc protein, mouse; C000605507:Gsk3b protein, mouse