Is Structural Remodeling of Fibrillated Atria the Consequence of Tissue Hypoxia?

Abstract

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. 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. It is possible that upregulation of HIF-1/VEGF is involved in the enhancement of MMP-9 expression under hypoxic conditions.