Hypoxia in Abdominal Aortic Aneurysm Supports a Role for HIF-1α and Ets-1 as Drivers of Matrix Metalloproteinase Upregulation in Human Aortic Smooth Muscle Cells
Background/Aims: We sought to determine whether hypoxia is an initiating factor in the matrix metalloproteinase-2 (MMP-2) up-regulation observed in abdominal aortic aneurysm (AAA) and whether hypoxia-inducible factor-1α (HIF-1α) or Ets-1 are mediating factors. Methods: Human AAA and normal aorta were analysed for MMP-2, HIF-1α and Ets-1 by immunohistochemistry. Human aortic smooth muscle cell (HASMC) cultures exposed to experimental hypoxia were analysed for hypoxia-induced proteins using gelatin zymography and immunoblotting. Multiplex PCR was used to detect MMP-1, membrane-type (MT)-MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9. Results: AAA tissues expressed HIF-1α, MMP-2 and Ets-1 strongly within smooth muscle cells and inflammatory infiltrate of the tunica media. Up-regulated MMP-2 was detected in hypoxia-exposed HASMC (p < 0.05), with MMP-9 elevations after exposure to sequential O2 decreases (p < 0.05). Immunoblotting confirmed HIF-1α, Ets-1, VEGF and MMP-2 are up-regulated in HASMC exposed to hypoxia (p < 0.05), while transcription for MMP-1, MT-MMP-1, MMP-9, MMP-2 and MMP-7 (p < 0.05) increased in hypoxic HASMCs. Conclusion: Hypoxia facilitates HIF-1α, Ets-1 and VEGF up-regulation in addition to driving enhanced secretion of MMP-2 and MMP-9 by HASMC. Enhanced transcription of factors relevant to aneurysmal disease in hypoxia indicates possible roles in disease progression and potential targets for therapeutic intervention.