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The Role Matrix Metalloproteinases in the Production of Aortic Aneurysm
1University of British Columbia, Vancouver, BC, Canada.
Abstract:
Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of aortic aneurysm because the histology of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) is characterized by the loss of smooth muscle cells in the aortic media and the destruction of extracellular matrix (ECM). Furthermore, AAA have evidence of inflammation and the cellular elements involved in inflammation such as macrophages can produce and/or activate MMPs This chapter focuses on human aortic aneurysm that are not due to specific known genetic causes because this type of aneurysm is the more common type. This chapter will also focus on MMP protein expression rather than on genetic data which may not necessarily translate to increased MMP protein expression. There are supporting data that certain MMPs are increased in the aortic wall. For TAA, it is most notably MMP-1, -9, -12, and -14 and MMP-2 when a bicuspid aortic valve is present. For AAA, it is MMP-1, -2, -3, -9, -12, and -13. The data are weaker or insufficient for the other MMPs. Several studies of gene polymorphisms support MMP-9 for TAA and MMP-3 for AAA as potentially important factors. The signaling pathways in the aorta that can lead to MMP activation include JNK, JAK/stat, osteopontin, and AMP-activated protein kinase alpha2. Substrates in the human vasculature for MMP-3, MMP-9, or MMP-14 include collagen, elastin, ECM glycoprotein, and proteoglycans. Confirmed and potential substrates for MMPs, maintain aortic size and function so that a reduction in their content relative to other components of the aortic wall may produce a failure to maintain aortic size leading to dilatation and aneurysm formation.
Insights
Matrix metalloproteinases (MMPs) are linked to aortic aneurysm development by degrading extracellular matrix. Specific MMPs like MMP-1, -9, and -12 are elevated in thoracic and abdominal aortic aneurysms, contributing to disease progression.
Area of Science:
- Cardiovascular Biology
- Biochemistry
- Pathology
Background:
- Aortic aneurysms, including thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA), involve smooth muscle cell loss and extracellular matrix (ECM) destruction.
- Inflammation, particularly macrophage activity, contributes to matrix metalloproteinase (MMP) production and activation in AAA.
- This focuses on common, non-genetic human aortic aneurysms, emphasizing MMP protein expression over genetic data.
Purpose of the Study:
- To investigate the role of specific matrix metalloproteinases (MMPs) in the pathogenesis of common human aortic aneurysms (TAA and AAA).
- To correlate MMP protein expression levels with histological changes and disease progression in aortic aneurysms.
- To identify key MMPs and their substrates involved in maintaining aortic integrity and their potential role in aneurysm formation.
Main Methods:
- Review and analysis of existing literature on MMP protein expression in human TAA and AAA.
- Correlation of identified MMPs with histological findings such as ECM destruction and smooth muscle cell loss.
- Examination of signaling pathways (JNK, JAK/stat, etc.) implicated in MMP activation within the aorta.
Main Results:
- Elevated expression of specific MMPs in TAA (MMP-1, -9, -12, -14; MMP-2 with bicuspid aortic valve) and AAA (MMP-1, -2, -3, -9, -12, -13).
- Supporting genetic data suggests MMP-9 for TAA and MMP-3 for AAA.
- Key vascular substrates for MMPs include collagen, elastin, ECM glycoproteins, and proteoglycans.
Conclusions:
- Increased MMP expression and activity are strongly implicated in the pathogenesis of TAA and AAA.
- Degradation of ECM components by MMPs compromises aortic wall integrity, leading to dilatation and aneurysm formation.
- Targeting specific MMPs or their substrates may offer therapeutic strategies for aortic aneurysm treatment.