Is structural remodeling of fibrillated atria the consequence of tissue hypoxia?
BACKGROUND
Matrix metalloproteinases (MMPs) play an important role in degradation of the extracellular matrix of injured tissue. MMP-9 expression increases in fibrillating atrial tissue; however, the mechanism for this increase has not been clarified.


RESULTS
Changes in the expression of vascular endothelial growth factor (VEGF), VEGF receptors, and hypoxia-induced transcription factor-1alpha (HIF-1alpha) in fibrillating atrial tissue were investigated. Atrial tissue samples were obtained from 13 patients with atrial fibrillation (AF) and 25 patients without a history of AF (regular sinus rhythm, RSR) undergoing cardiac operations. Western blot, real-time polymerase chain reaction, and immunofluorescence analyses of the expression of VEGF, VEGF receptors, and HIF-1alpha were performed. The VEGF mRNA and protein levels increased significantly in the AF group compared with the RSR group (P<0.05), and the expression of HIF-1alpha protein was also significantly higher in the AF group. VEGF receptor-1 mRNA, a high-affinity receptor for VEGF, but not VEGF receptor-2 mRNA, was upregulated in the atria of the AF group (P<0.05). Immunofluorescence staining revealed excess production and co-localization of HIF-1alpha, VEGF and MMP-9 in the endothelium of the atrial arteries in the AF group.


CONCLUSIONS
It is possible that upregulation of HIF-1/VEGF is involved in the enhancement of MMP-9 expression under hypoxic conditions.
Ogi
Hiroshi
H
Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Science, Hiroshima, Japan.
Nakano
Yukiko
Y
Niida
Shumpei
S
Dote
Keigo
K
Hirai
Yukoh
Y
Suenari
Kazuyosi
K
Tonouchi
Yukiji
Y
Oda
Noboru
N
Makita
Yuko
Y
Ueda
Shigeyuki
S
Kajihara
Kenta
K
Imai
Katsuhiko
K
Sueda
Taijro
T
Chayama
Kazuaki
K
Kihara
Yasuki
Y
D000368:Aged; D001281:Atrial Fibrillation / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000235:genetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis* / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9