The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms

Abstract

Abdominal aortic aneurysms (AAAs) account for up to 8% of deaths in men aged 65 years and over and 2.2% of women. Patients with AAAs often have atherosclerosis, and intimal atherosclerosis is generally present in AAAs. Accordingly, AAAs are considered a form of atherosclerosis and are frequently referred to as atherosclerotic aneurysms. Pathological observations advocate inflammatory cell infiltration alongside adverse extracellular matrix degradation as key contributing factors to the formation of human atherosclerotic AAAs. Therefore, macrophage production of proteolytic enzymes is deemed responsible for the damaging loss of ECM proteins, especially elastin and fibrillar collagens, which characterise AAA progression and rupture. Matrix metalloproteinases (MMPs) and their regulation by tissue inhibitors metalloproteinases (TIMPs) can orchestrate not only ECM remodelling, but also moderate the proliferation, migration, and apoptosis of resident aortic cells, alongside the recruitment and subsequent behaviour of inflammatory cells. Accordingly, MMPs are thought to play a central regulatory role in the development, progression, and eventual rupture of abdominal aortic aneurysms (AAAs). Together, clinical and animal studies have shed light on the complex and often diverse effects MMPs and TIMPs impart during the development of AAAs. This dichotomy is underlined from evidence utilising broad-spectrum MMP inhibition in animal models and clinical trials which have failed to provide consistent protection from AAA progression, although more encouraging results have been observed through deployment of selective inhibitors. This review provides a summary of the supporting evidence connecting the contribution of individual MMPs to AAA development, progression, and eventual rupture. Topics discussed include structural, functional, and cell-specific diversity of MMP members; evidence from animal models of AAA and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the advances in identifying aberrant MMP activity. As evidenced, our developing understanding of the multifaceted roles individual MMPs perform during the progression and rupture of AAAs, should motivate clinical trials assessing the therapeutic potential of selective MMP inhibitors, which could restrict AAA-related morbidity and mortality worldwide.

Glutamine Protects against Mouse Abdominal Aortic Aneurysm through Modulating VSMC Apoptosis and M1 Macrophage Activation

“…VSMC apoptosis in physiological conditions is beneficial for normal functions of vessels, however, excessive VSMC apoptosis due to overproduction of MMP and ROS inevitably damages the structure of abdominal aorta, gradually leading to the formation and progression of AAA 17 - 19 . In this study, the TUNEL assay showed that glutamine decreased the level of apoptosis in AngII-infused suprarenal abdominal aortas (Figure 6 A and 6 B).…”

“…MMP has long been thought to play a central regulatory role in development, progression, and eventual rupture of AAA, since it promoted the degradation of extracellular matrix (ECM), especially among which the rupture of elastic fiber led to the structure destruction of abdominal aorta, finally causing sudden rupture of the aneurysm and life-threatening massive bleeding 15 , 16 . Additionally, MMP itself could result in apoptosis of resident aortic cells and mass infiltration of inflammatory cells in aortic tissues 17 . ROS in physiological levels played an important role in maintaining normal vascular functions like VSMC contraction, while uncontrolled overproduction of ROS resulted in oxidative stress, causing vascular damage, the recruitment of inflammatory cells, and activation of MMP, finally leading to numerous vascular diseases including AAA 18 , 19 .…”

Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice

“…While our interventional findings utilizing pharmacological MMP-12 inhibition support a detrimental role for this protease, several studies evaluating the effect of MMP-12 deficiency in a range of mouse aneurysm models have yielded inconsistent findings [ 15 ]. Consistent with our own observations and supporting a detrimental role for MMP-12 in AAA, whole body deletion of MMP-12 reduced aneurysm growth elicited through adventitial CaCl 2 application to wild-type mice, as evidenced by reduced elastin fragmentation and aortic dilation, in comparison to untreated control animals [ 26 ].…”

“…Numerous studies deploying broad-spectrum MMP inhibitors in varying rodent models have demonstrated that indiscriminate metalloproteinase inhibition limits the development of AAAs [ 15 ]. However, such positive outcomes have not been replicated in clinical trials, which have focused upon tetracycline derivatives as broad-spectrum MMP inhibitors [ 15 ]. These disappointing results suggest that therapeutically targeting discrete MMPs may prove more effective.…”

“…Given that macrophage accumulation at both the adventitial and medial aspects is a striking feature of human atherosclerotic AAA [ 14 ], the principle detrimental role of macrophages in atherosclerotic AAA is considered to be through their release of proteolytic enzymes such as matrix metalloproteinases (MMPs) [ 15 ]. In turn, MMPs are apportioned responsibility for the excessive loss of ECM proteins observed within AAAs, especially elastin and fibrillar collagens, which characterize AAA progression and rupture [ 14 ].…”