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

Abstract

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.

Interaction of Biomechanics with Extracellular Matrix Components in Abdominal Aortic Aneurysm Wall

“…14 Furthermore, it has been discussed that ILT may contribute to wall hypoxia and that the decrease of collagen synthesis upregulates the activation of MMP. 37 Moreover, AAA local and normalized local diameter (NORD) correlated negatively with elastin, but not with collagens. This expected result indicates that elastin does not contribute to repair processes because of the almost non-existent level of synthesis of new elastin in the adult aorta.…”

The Role of Hypoxia Inducible Factor-1 in Hepatocellular Carcinoma

“…When tumors encounter low oxygen tension, HIF-1 acts as a transcription factor upregulating the expression of MMPs in both mRNA and protein levels [69, 70]. In contrast, silencing of HIF-1 inhibits cellular metastasis through alteration of invasion-related enzymes such as MMP-2 and MMP-9, both of which are decreased with the introduction of HIF-1 α small interfering RNA (siRNA) [71].…”

Transcriptional regulation by hypoxia inducible factors

“…More recently, activation of HIFs in fat adipose tissue was implicated in the development of dietary obesity, a key risk factor for type II diabetes (Krishnan et al, 2012). HIFs have also been linked to other pathologies, such as atherosclerosis, pulmonary hypertension and abdominal aortic aneurysm formation (Erdozain et al, 2011, Semenza, 2012a). Thus, a detailed understanding of the molecular mechanism of action of HIFs will advance multiple areas of biomedical research.…”