Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm
Clinical & Experimental Cardiology

Clinical & Experimental Cardiology
Open Access

ISSN: 2155-9880

Review Article - (2013) Volume 4, Issue 8

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

Ratnadeep Basu1,2 and Zamaneh Kassiri1,2*
1Department of Physiology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
2Cardiovascular Research Center, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
*Corresponding Author: Zamaneh Kassiri, PhD, Associate Professor, Department of Physiology, University of Alberta, 474 HMRC, Edmonton, AB, T6G 2S2, Canada, Tel: (780) 492-9283 (Office); (780) 492-8673, Fax: (780) 492-9753 Email:


Aorta is the largest artery in the body. Aortic wall is comprised of an intricate arrangement of extracellular matrix (ECM) structural proteins, primarily collagen and elastin, and layers of vascular smooth muscle cells. This gives the aortic wall the tensile strength to withstand the pressure of blood pumped from the heart during systole, and the elasticity to expand and accommodate the left ventricular stroke volume and to, subsequently, recoil to its original diameter and push the blood forward for systemic perfusion. Aortic aneurysm involves structural degradation of the aortic wall and focal dilatation of the aortic lumen. It is a devastating health problem with no effective treatment. Current management strategies for AAA patients include antihypertensive drugs and surgical repair for severe cases of AAA which are not without limitations and complications. A number of proteases (matrix metalloproteinases, serine and cystein proteases), and their inhibitors (tissue inhibitor of metalloproteases and cystatin) have been shown to contribute to AAA development and progression. In this review we will summarize the published literature on the role of ECM-regulatory proteins, mainly proteases and their inhibitors, in aortic function and aneurysm formation, with a focus on abdominal aortic aneurysm.

Keywords: Abdominal aortic aneurysm; Vascular matrix; Matrix metalloprotease; Tissue inhibitor of metalloproteinase; Atherosclerosis


Aorta, the largest artery in the body, does not merely serve as a conduit to distribute blood from the heart to the body, but plays important roles in multiple aspects of the cardiovascular system, including perfusion of the myocardium and the peripheral tissue, and arterial function [1]. During cardiac systole, aorta expands to store a large proportion of the left ventricular stroke volume while during diastole, recoil of the aortic wall pushes the stored blood forward and into the periphery. This function of the aorta as a ‘mini-pump’ maintains blood flow and pressure throughout the cardiac cycle. The storage capacity of the aorta is directly related to the mechanical properties of the aortic wall. When the aorta becomes stiff, it loses its ability to expand compromising its storage capacity, while loss of its elasticity will reduce its ability to recoil during cardiac diastole and to push forward the blood stored during systole.

Aortic Wall Structure and Composition

Similar to smaller arteries, aortic wall is comprised of three layers, intima, media and adventitia [2,3]. Intima is a single layer of endothelial cells that make up the luminal surface of the aorta. Media is comprised of layers of elastin arranged in fenestrated sheets called ‘lamellae’, collagen fibers, thin layers of proteoglycan-rich extracellular matrix (ECM) and smooth muscle cells (VSMCs) that are embedded in this matrix of structural proteins. Media provides the tensile strength and recoil ability of the aorta. During development, media grows differently in thoracic versus the abdominal aorta. During growth, medial thickness increases by an increase in the number of lamellar units in thoracic aorta, whereas in abdominal aorta each unit widens [4]. In both regions however, a constant aortic diameter-to-medial thickness is maintained which determines wall stress and tension per lamellar unit [5]. Adventitia is the outermost layer of the aortic wall and is comprised primarily of collagen and differentiated from the media by external lamina. Structure of the aortic wall is a major determinant of its function. While the total amount of the main matrix proteins, collagen and elastin, is approximately the same throughout the aorta, thoracic aorta contains more elastin than collagen, whereas more collagen is present in the abdominal aorta than elastin [1,6]. Aortic wall is supplied with a rich network of innervations and vasa vasorum, small blood vessels that supply blood to the adventitia and the outer aortic wall. Vasa vasorum structure is more extensive in the thoracic than the abdominal aorta. Any change in the structure of the aortic wall may result in alterations in the aortic function. Aortic aneurysm results from structural degradation of the aortic wall leading to focal dilation which expands and eventually ruptures. In this review we will summarize the published work on aortic aneurysm with a focus on abdominal aortic aneurysm, and will discuss the contribution of the enzymes and proteins that directly regulate the remodeling of the aortic wall matrix structure. We will also discuss the findings in patients and animal models of aortic aneurysm, and finally will touch on possible treatments for this devastating health condition.

Aortic aneurysm

Aortic aneurysm is defined as a focal dilation of more than 50% of its original diameter. Aortic aneurysm can develop in thoracic or abdominal region of the aorta, each with unique pathology and molecular signatures [5]. Aortic aneurysm is often asymptomatic until it ruptures causing significant morbidity and greater than 80% mortality which accounts for 1-2% of total death in the industrialized countries [7-9]. Other complications of aortic aneurysm include dissection (tearing of the intimal wall with entry of luminal blood into the wall), embolism, or compression of an adjacent structure. Abdominal aortic aneurysm (AAA) is the more prevalent form of aneurysm affecting approximately 6-8% of men aged over 60, compared to thoracic abdominal aneurysm (TAA) that affects 5 to 6 in 100,000 individuals [5,10-12]. Both types of aneurysm are more common in men than in women [11] although prognosis of AAA is worse in women compared to men with higher rupture rates [13]. So far there has been no effective pharmacological treatment for aortic aneurysm [10]. Surgical repair (open surgical repair and endovascular repair) can stabilize large aneurysms but are often limited to cases where the risk of rupture exceeds that of the surgical intervention [5], and even then subsequent mortality and morbidity remain high [10,12]. In addition, aortic stenting has been shown to trigger neointimal growth adverse remodeling which could lead to aneurysm formation, although the stent material can be a major determinant of the outcome [14].

The main cause of aneurysm is structural damage to the media and adventitia and loss of VSMCs [15], leading to hemodynamic changes, increased wall stress, lumen dilatation and eventually rupture of the aortic wall. This can explain the higher prevalence of aneurysm in the abdominal aorta which contains a lower number of lamellar units, decreased elastin content and poorer vasa vasorum supply of nutrients and oxygen to the SMC. In addition, inflammation seems to be a prominent contributor to AAA expansion [16-18].

A multi-stage paradigm has been proposed for AAA growth and rupture according to which, loss of elastin mediated by proteases produced from VSMC is the initiating event, followed by influx of inflammatory cells (leukocytes) in response to the production of ECM fragments with chemotactic activity. The inflammatory cells also produce a number of proteases which further contribute to destabilization of the aortic wall [19]. Further, initial loss of elastin in the medial layer causes compensatory fibrosis leading to normal or increased collagen deposition, and increased stiffness of the aorta. At later stages, destruction of all major matrix components, as a consequence of inflammation, causes further expansion and eventually rupture.

Vascular ECM remodelling in AAA

Vascular ECM is a dynamic structure with continuous turnover whereby existing structural proteins are replaced with newly synthesized proteins. Therefore, any change in the vascular environment can be reflected in the ECM composition that attempts to maintain a homeostatic environment for optimal function. VSMCs have been identified as the main source for ECM proteins [3] that determine the mechanical properties of the arterial wall. Collagen fibres in the aortic wall provides the tensile strength required for the inflation of the wall during cardiac systole without rupture, while elastin lamella underlie the recoil property of the aorta which is essential during cardiac diastole. This elasticity of the aorta is nonlinear which accommodates the increasing pressure without rupture of the aortic wall during systole. Compromised integrity of the vascular ECM can result from impaired synthesis of ECM structural proteins or aberrant proteolysis. The most common cases of aortic aneurysm secondary to impaired ECM synthesis is Marfan syndrome, a genetic disease caused by a mutation in the gene encoding fibrililn-1, a critical component for proper assembly of elastin in the aortic wall. Although abdominal aortic aneurysm has been reported in patients with Marfan syndrome, thoracic aortic dilation and rupture is the most common form of aortopathy in these patients [20,21]. Excellent reviews have been published on thoracic aortic aneurysm [20,22,23], in this review we will focus on the mechanisms that underlie AAA development.

In AAA, the structural degradation of the aortic wall impairs these mechanical properties of the aorta, emphasizing the key role of proteases that have been found to be elevated in the aneurysmal tissue in this process [5,18]. Among the different classes of proteases, matrix metalloproteases (MMPs), serine and cysteine proteases have been found to contribute to aortic aneurysm formation (Table 1).

Mouse strain Aneurysm Model Phenotype Ref.
MMP2-/- CaCl2, abdominal Protection against AAA [46]
MMP3-/-/ApoE-/- Cholesterol rich diet Reduced thoracic and abdominal aneurysm formation (sustained atherosclerotic plaque). [58]
MMP8-/- Elastase, abdominal No change in AAA size [59]
MMP9-/- CaCl2, thoracic CaCl2, abdominal Elastase, abdominal Attenuated TAA Protection against AAA Protection against AAA [56]
MMP12-/- CaCl2, abdominal Elastase, abdominal Ang II + anti-TGFb Attenuated AAA No change in AAA size Protection against AAA [60]
MMP13-/- Elastase, abdominal Reduced AAA aortic dilation [97]
Cathepsin K-/- Cathepsin K-/-/ApoE-/- Elastase, abdominal Ang II + high fat diet Reduced AAA dilation Unchanged AAA [64]
Cystatin C-/-/ApoE-/- Ang II + high fat diet Exacerbated AAA dilation [66]
MCP4-/- (mast cell protein-4, Chymase) Elastase, abdominal Reduced AAA dilation [68]
Plg-/- CaCl2, abdominal Protected against AAA [70]
TIMP1-/- CaCl2, Thoracic Exacerbated TAA. [74]
TIMP1-/-/ApoE-/- Cholesterol-rich diet Enhanced thoracic and abdominal aneurysm formation, (reduced atherosclerotic plaque) [73]
TIMP2-/- CaCl2, abdominal Attenuated AAA [75]
TIMP3-/- Ang II infusion Suprarenal AAA formation [48]
TIMP3-/-/MMP2-/- Ang II infusion Exacerbated AAA dilation [48]

Table 1: Summary of abdominal aortic aneurysm formation in protease or TIMP-deficient mouse models. AAA = abdominal aortic aneurysm; ApoE = apolipoprotein E; CaCl2=calcium chloride; MCP-4 = mast cell protein-4; MMP = matrix metalloproteinase; plg = plasminogen; TAA = thoracic aortic aneurysm; TIMP = tissue inhibitor of matrix metalloproteinase.

Matrix metalloproteases and their inhibitors in AAA

Matrix metalloproteinases (MMPs) constitute a family of more than 25 soluble and transmembrane enzymes which play an important role in ECM turnover. Function of MMPs is balanced by their inhibitors, tissue inhibitor of metalloproteinase (TIMPs) to achieve optimal ECM composition [24]. Impairment of this delicate balance is fundamental to the pathogenesis of aortic aneurysm formation, expansion and rupture [5,15,25-28]. TIMPs comprise s group of proteins of molecular weight ranging from 21-30 kDa that serve as potent endogenous inhibitors of MMPs through a covalent bond between their N-terminus and the catalytic domain in the activated MMPs [24]. All four TIMPs (TIMP1- 4) are found in vertebrates and their expression levels are modulated during tissue remodelling or development [29]. TIMP3 is unique as it is the only TIMP bound to the ECM via its C terminal domain that provides extra reservoir by prolonging its half life [30] and has a broad inhibitory substrate profile which includes a number of disintegrin and metalloproteinase (ADAMs) [24,31].

In AAA samples from patients, MMP1 and MMP9 mRNA levels were elevated compared to non-aneurysmal aorta [32,33], while MMP1, MMP12 and MT1-MMP proteins levels were also elevated [34]. Among 14 MMPs and 4 TIMPs analyzed in samples of aortic wall from patients with AAA, only stromelysin-1 (MMP3) and TIMP3 were found to be elevated [35]. MMP12, also known as macrophage elastase, has been reported to be prominently produced by aneurysminfiltrating macrophages, and localized within the degenerating aortic media of AAA, where is it bound to residual elastic fragments [36].

Differing reports on levels of TIMPs in AAA have been made. Studies on AAA biopsies from patients have shown increased TIMP1 and TIMP2 mRNA levels [32], unaltered TIMP2 [33], and elevated TIMP3 with unaltered TIMP1 and TIMP2 levels [34]. While TIMP1 inhibits a large number of MMPs, it does not inhibit MT1-MMP [37]. TIMP2 is a potent inhibitor of MMP2 and MT1-MMP [38], but in a dose-dependent manner can also activate pro-MMP2 through formation of a trimolecular complex with MT1-MMP [39]. A few studies have utilized the ratio of MMP2 to TIMP2 levels as another index of proteolysis in the ECM [32,40] although this approach does not account for contribution of TIMPs such as TIMP3 and TIMP4 which are also potent inhibitors of MMP2.

It is important to note that the data available from AAA patients are achieved at the late stages of disease, and the patients are often receiving medications that could alter the molecular events in the aortic tissue. Lack of availability of aortic tissue samples during the early stages of AAA is a limiting factor in developing an effective treatment for this disease. Animal models provide a valuable tool to explore and determine the early contributors to disease development and progression with the ultimate aim of preventing the disease or hindering its progress.

Experimental models of AAA targeting proteases and their inhibitors

Animal models of AAA have been implemented to recapitulate features of AAA in humans such as adverse ECM remodelling, medial degeneration, inflammation, thrombus formation and rupture. AAA models in rats were reported over 2 decades ago [41] and since then AAA has been generated and studied in different rodent models [42-44], however mouse models have gained dominance over others primarily due to availability of genetically modified mice [18]. Three most common experimental models of AAA include transient intraluminal infusion of elastase (a pancreatic extract) [45], adventitial exposure of a high concentration CaCl2 solution [46], or chronic subcutaneous infusion of a hypertensive dose of Angiotensin II (Ang II) in a hypercholestremic [47] or normocholestremic background [48]. Hypercholestremia in mice is achieved by deficiency of apolipoprotein-E (ApoE) or low density lipoprotein receptor (LDLR) combined with high fat or high cholesterol diet [49-51]. The Ang II infusion model allows for detection of aneurysm throughout the aorta while the elastase infusion and CaCl2 exposure models provide information about regional aortic susceptibility.

The growing list of genetically modified mice with targeted MMPs, proteases, or TIMPs subjected to different models of aortic aneurysm provide valuable insight into the role of these ECM-regulatory proteins in development and progression of AAA (Table 1). In addition to the proteases produced by VSMCs, infiltrating inflammatory cells can contribute to enhanced proteolysis in the aortic wall. Neutrophils generate MMP8, MMP9 [52,53] and MT6-MMP(MMP25) [54], while macrophages produce a number of MMPs including MMP-1, -3, -7, -8, -9 and -12 [55]. Mice deficient in either MMP2 or MMP9 did not develop AAA following CaCl2 treatment [46]. Similarly, MMP9-/- mice showed attenuated TAA induced by CaCl2 despite a significant rise in MMP2 [56]. Reconstitution of wild type macrophages led to the development of AAA in MMP9-/- but not in MMP2-/- mice [46], demonstrating that an interaction between MMP9 produced by macrophages and MMP2 from native VSMCs is required for development of AAA. Deficiency of macrophage-derived MT1-MMP [57] also attenuated CaCl2- induced AAAs in mice, indicating that multiple macrophage-derived factors can contribute to AAA formation. MMP3 deficiency reduced frequency of aortic aneurysm formation in hypercholestremic ApoE-/- mice despite sustained prevalence of atherosclerotic lesions [58]. MMP8 deficiency in mice did not alter the size of elastase-induced AAAs, whereas neutrophil depletion prevented AAA through a mechanism independent from MMP2 and MMP9 pathways [59].This study demonstrates that additional factors produced by neutrophils (e.g. neutrophil elastase) are essential in AAA formation. Interestingly, deficiency in MMP12 a macrophages-derived elastase, improved CaCl2-induced AAA [60], but not elastase-induced AAA in mice [45].

Non-MMP cysteine and serine proteases also contribute to the proteolytic degradation of the aortic wall in AAA. Cathepsin K, L and S, all cystein proteases have been found in AAA tissues from patients [61,62]. Cathepsin S and K are potent elastases that are produced by VSMCs and macrophages in atherosclerotic plaques, and have been found at the site of arterial elastin damage [63]. Cathepsin K-deficiency attenuated elastase-induced AAA [64], but not Ang II-induced AAA in ApeoE-/- high fat-fed mice [49]. Calpain is another cystein protease that is elevated in response to Ang II in ApoE-deficient atherosclerotic mice, and its pharmacological inhibition reduced AAA in these mice [65]. Cystatin C is an inhibitor of cysteine proteases and is expressed in healthy VSMCs but severely reduced in atherosclerotic plaques as well as aneurysmal tissue from AAA patients [62]. Cystatin C-deficiency exacerbated Ang II-induced AAA in atherosclerotic mice [66].

Among serine proteases, role of chymases and plasminogen activators have been studied in AAA. Chymases are mast-cell restricted serine proteases that have been shown to activate MMP9 in AAA patients [67]. Deficiency in MCP4 (mast cell protease 4) but not MCP5 reduced AAA formation up to 8 weeks after elastase infusion [68]. Plasminogen binds to the ECM and upon conversion to plasmin, by tissue or urokinase plasminogen activator (uPA or tPA), degrades multiple ECM proteins through activation of collagenases. In addition, tPA can release degradulate neutrophils and release neutrophil MMPs and elastase [53]. Plasminogen-deficiency attenuated CaCl2-induced AAA in mice through reduced trans-ECM migration of macrophages and decreased MMP9 activation [69]. Moreover, deficiency in uPA, but not tPA, abrogated aortic aneurysm formation in hypercholestremic ApoE-/- deficient mice through inhibiting activation of MMP3, MMP9 and MMP13 [70]. Interestingly, in a recent study it was reported that tobacco smoke exposure exacerbates AAA independent of elastase activity but possibly through recruiting leukocytes [71].

TIMP1 was the first TIMP whose role in aortic aneurysm was examined. In a hypercholestremic mice, TIMP1 deficiency led to increased incidence of aortic aneurysm but reduced formation of atherosclerotic plaque lesions [72]. Consistently, a CaCl2 model of TAA showed more severe aneurysm progression in TIMP1-/- mice with continual dilatation of the aorta up to 8 weeks after CaCl2 treatment, whereas in parallel wildtype mice aortic dilatation plateaued by 4 weeks [73]. TIMP2-deficiency however proved to be beneficial in a CaCl2 model of AAA [74]. This beneficial effect was attributed to reduced conversion of pro-MMP2 (72 kDa) to its cleaved (64 kDa). Role of TIMP3 in aortic aneurysm has been reported recently in a model of Ang II infusion in the absence of any metabolic phenotypes. Infusion of TIMP3-/- mice with a hypertensive dose of Ang II resulted in a suppressed hypertensive response [75], but development of AAA after 4 weeks of Ang II infusion, whereas wildtype mice, that had increased TIMP3 levels in the abdominal aorta, did not exhibit AAA [48], suggesting a protective function of TIMP3 in this process (Figure 1). Although elevated MMP2 activation was detected in the abdominal aorta after 2 weeks of Ang II infusion, ablation of MMP2 in TIMP3-/- mice exacerbated AAA dilation and increased the rate of aortic rupture, primarily due to heightened inflammation. Treatment with a broad spectrum MMP inhibitor (PD166793) prevented AAA formation in TIMP3-/- and TIMP3-/-/MMP2-/- mice [48].


Figure 1: Lack of TIMP3 increases susceptibility to AAA in the absence of metabolic syndrome. A) representative images of mouse aorta showing that 4 weeks of Ang II infusion (1.5 mg/Kg/day) resulted in AAA formation in TIMP3-/- but not in WT mice. (Modified from [48]). B) TIMP3-/--Ang II mice exhibited 18% mortality due to aortic rupture in the suprarenal region where aneurysm was detected. C) Different morphologies of AAA in TIMP3-/--Ang II mice. D) Schematic of molecular events leading to AAA in the absence of TIMP3.

Overall, these studies demonstrate that distinct molecular mechanisms are involved in different models of aortic aneurysm, and while it was once believed that generally a reduction in MMPs and increase in TIMPs would provide beneficial effects, it is important to acknowledge that the interaction between these molecules is quite complex and deserves detailed investigation in different AAA models .

Aortic aneurysm occurs independently from hypertension and atherosclerosis

Although it was initially believed that AAA was the consequence of advanced atherosclerosis [76], it has become increasingly evident that there is no causal link between atherosclerosis and AAA [12]. While age, gender and body surface area have been found to be major determinants of aortic dimensions, aortic atherosclerotic plaques were weakly associated with aortic dilatation risk factors [77]. Tromso study reported that among the 6446 men and women studied, consistent dose-response relationship was not found between atherosclerosis and abdominal aortic diameter, suggesting that atherosclerosis is not the causal event in AAA development but perhaps occurs in parallel or secondary to aneurysmal dilatation [78]. Consistently, therapies against atherosclerosis have not been effective in treating AAA in humans [10,79]. Animal studies have been in agreement with these findings as a clear dissociation between atherosclerotic lesions and aortic aneurysm formation has been reported [58,72,80]. MMP3-/-/ApoE-/- mice (on cholesterol-rich diet) showed reduced frequency of aortic aneurysm formation despite sustained prevalence of atherosclerotic lesions compared to ApoeE-/- mice [58]. Conversely, hypercholestremic TIMP1-/-/ApoE-/- mice showed increased incidence of aortic aneurysm but reduced formation of atherosclerotic plaque lesions [72].

Hypertension is another co-morbidity but independent from AAA development. Ang II-mediated AAA formation in ApoE-/- and LDLR-/- mice was independent of the blood pressure as suppression of hypertension (by hydralazin administration) did not prevent AAA or atheroscrlerosis in these mice [51]. Recently, we reported that despite the suppressed Ang II-induced hypertension in TIMP3-/- mice, these mice develop AAA after 4 weeks of Ang II infusion while WT mice did not [48]. Overall, sufficient evidence indicate ECM degradation and as the central and initiating event in development of AAA, while comorbidities such as atherosclerosis and hypertension may or may not be present with AAA.

Doxycycline, a potential treatment for aortic aneurysm

Over that past few decades a number of drugs have been used to treat AAA, however the search continues. Beta-receptor blockers, angiotensin-converting enzyme (ACE) inhibitors and statins have not shown consistent beneficial effects in patients [10,81]. Inhibition of c-Jun N terminal kinase (JNK) prevented formation of aneurysm in a CaCl2 model of AAA [82], however clinical efficacy of this approach remains to be determined. Doxycycline, a member of the tetracycline group, has been receiving a lot of attention as a potential treatment for AAA. The MMP-inhibitory function of tetracyclines was first discovered in early 1980’s [83]. Doxycycline is a member of the tetracycline antibiotic group commonly used to treat infections, and has been approved by FDA as an MMP-inhibitor in periodontal diseases [84,85]. Doxycycline has been shown to exert beneficial effects in a number of animal studies including the elastase-infusion model of AAA in rats [86,87] and mice [45], CaCl2-induced AAAs in mice [88], and in AngII-infused hypercholestremic mice where it markedly reduced the rate of development of AAA, aortic diameter and aortic rupture without altering atherosclrotic plaque formation [89,90]. However, a recent study reported that doxycycline treatment did not prevent progression of established AAA in hypercholestremic mice [91].

Reports on the beneficial effects of doxycycline treatment in AAA patients appear promising in controlling AAA expansion, although not its regression. Prolonged administration of doxycycline was well tolerated by AAA patients [92]. A randomized trial in patients awaiting open AAA repair showed that 2 weeks of doxycycline treatment reduced inflammation in AAA biopsies [93], while a randomized trial in patients who underwent endovascular AAA repair showed that doxycycline reduced circulating levels of MMPs which were suggested to be a marker of endograft failure [94]. Currently two larger randomised trials are examining the efficacy of doxycycline in patients with small AAAs, with one of these studies expected to report in 2014 [10]. Since non-MMP proteases have also been shown to contribute to AAA development and progression, incorporation of other protease inhibitors with doxycycline could result in synergistic beneficial effects.


Aortic aneurysm remains a major health burden which due to it asymptomatic nature often is undetected until it ruptures causing devastating morbidities, and mortality. AAA results from structural degradation of the aortic wall due to uncontrolled proteolysis. Protease inhibitors such as doxycycline appear to be a promising treatment for AAA although it remains to be determined whether doxycycline can reverse aortic dilation in AAA patients. In addition, since non-MMP proteases also contribute to AAA development and progression, a combination-therapy incorporating other protease inhibitors with doxycycline could convey synergistic beneficial effects.


This article was supported by a grant from Canadian Institute for Health Research (CIHR, 84279). R.B. is supported by Graduate Scholarship from Alberta Innovates-Health Solutions (AI-HS). Z.K. is an AI-HS Scholar.


  1. Boudoulas KD, Vlachopoulos C, Raman SV, Sparks EA, Triposciadis F, et al. (2012) Aortic function: from the research laboratory to the clinic. Cardiology 121: 31-42.
  2. Tsamis A, Krawiec JT, Vorp DA (2013) Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review. J R Soc Interface 10: 20121004.
  3. Wagenseil JE, Mecham RP (2009) Vascular extracellular matrix and arterial mechanics. Physiol Rev 89: 957-989.
  4. Halloran BG, Davis VA, McManus BM, Lynch TG, Baxter BT (1995) Localization of aortic disease is associated with intrinsic differences in aortic structure. J Surg Res 59: 17-22.
  5. Ruddy JM, Jones JA, Spinale FG, Ikonomidis JS (2008) Regional heterogeneity within the aorta: relevance to aneurysm disease. J Thorac Cardiovasc Surg 136: 1123-1130.
  6. Sokolis DP, Boudoulas H, Karayannacos PE (2008) Segmental differences of aortic function and composition: clinical implications. Hellenic J Cardiol 49: 145-154.
  7. Best VA, Price JF, Fowkes FG (2003) Persistent increase in the incidence of abdominal aortic aneurysm in Scotland, 1981-2000. Br J Surg 90: 1510-1515.
  8. Filipovic M, Goldacre MJ, Roberts SE, Yeates D, Duncan ME, et al. (2005) Trends in mortality and hospital admission rates for abdominal aortic aneurysm in England and Wales, 1979-1999. Br J Surg 92: 968-975.
  9. Lindsay ME, Dietz HC (2011) Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 473: 308-316.
  10. Golledge J, Norman PE (2011) Current status of medical management for abdominal aortic aneurysm. Atherosclerosis 217: 57-63.
  11. Lederle FA, Johnson GR, Wilson SE, Chute EP, Littooy FN, et al. (1997) Prevalence and associations of abdominal aortic aneurysm detected through screening. Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study Group. Ann Intern Med 126: 441-449.
  12. Nordon IM, Hinchliffe RJ, Loftus IM, Thompson MM (2011) Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol 8: 92-102.
  13. Wanhainen A, Lundkvist J, Bergqvist D, Björck M (2006) Cost-effectiveness of screening women for abdominal aortic aneurysm. J Vasc Surg 43: 908-914.
  14. Maeng M, Jensen LO, Falk E, Andersen HR, Thuesen L (2009) Negative vascular remodelling after implantation of bioabsorbable magnesium alloy stents in porcine coronary arteries: a randomised comparison with bare-metal and sirolimus-eluting stents. Heart 95: 241-246.
  15. Dobrin PB, Mrkvicka R (1994) Failure of elastin or collagen as possible critical connective tissue alterations underlying aneurysmal dilatation. Cardiovasc Surg 2: 484-488.
  16. Galle C, Schandené L, Stordeur P, Peignois Y, Ferreira J, et al. (2005) Predominance of type 1 CD4+ T cells in human abdominal aortic aneurysm. Clin Exp Immunol 142: 519-527.
  17. Schönbeck U, Sukhova GK, Gerdes N, Libby P (2002) T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. Am J Pathol 161: 499-506.
  18. Lu H, Rateri DL, Bruemmer D, Cassis LA, Daugherty A (2012) Novel mechanisms of abdominal aortic aneurysms. Curr Atheroscler Rep 14: 402-412.
  19. Newby AC (2012) Matrix metalloproteinase inhibition therapy for vascular diseases. Vascul Pharmacol 56: 232-244.
  20. Bolar N, Van Laer L, Loeys BL (2012) Marfan syndrome: from gene to therapy. Curr Opin Pediatr 24: 498-504.
  21. Jondeau G, Detaint D, Tubach F, Arnoult F, Milleron O, et al. (2012) Aortic event rate in the Marfan population: a cohort study. Circulation 125: 226-232.
  22. Schoenhoff F, Schmidli J, Czerny M, Carrel TP (2013) Management of aortic aneurysms in patients with connective tissue disease. J Cardiovasc Surg (Torino) 54: 125-134.
  23. Theruvath TP, Jones JA, Ikonomidis JS (2012) Matrix metalloproteinases and descending aortic aneurysms: parity, disparity, and switch. J Card Surg 27: 81-90.
  24. Moore L, Fan D, Basu R, Kandalam V, Kassiri Z (2012) Tissue inhibitor of metalloproteinases (TIMPs) in heart failure. Heart Fail Rev 17: 693-706.
  25. Brophy CM, Marks WH, Reilly JM, Tilson MD (1991) Decreased tissue inhibitor of metalloproteinases (TIMP) in abdominal aortic aneurysm tissue: a preliminary report. J Surg Res 50: 653-657.
  26. McMillan WD, Tamarina NA, Cipollone M, Johnson DA, Parker MA, et al. (1997) Size matters: the relationship between MMP-9 expression and aortic diameter. Circulation 96: 2228-2232.
  27. Wilson WR, Anderton M, Schwalbe EC, Jones JL, Furness PN, et al. (2006) Matrix metalloproteinase-8 and -9 are increased at the site of abdominal aortic aneurysm rupture. Circulation 113: 438-445.
  28. Saratzis A, Abbas AA, Kiskinis D, Melas N, Saratzis N, et al. (2011) Abdominal aortic aneurysm: a review of the genetic basis. Angiology 62: 18-32.
  29. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477: 267-283.
  30. Dodd BR, Spence RA (2011) Doxycycline inhibition of abdominal aortic aneurysm growth: a systematic review of the literature. Curr Vasc Pharmacol 9: 471-478.
  31. Kashiwagi M, Tortorella M, Nagase H, Brew K (2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 276: 12501-12504.
  32. Tamarina NA, McMillan WD, Shively VP, Pearce WH (1997) Expression of matrix metalloproteinases and their inhibitors in aneurysms and normal aorta. Surgery 122: 264-271.
  33. McMillan WD, Patterson BK, Keen RR, Pearce WH (1995) In situ localization and quantification of seventy-two-kilodalton type IV collagenase in aneurysmal, occlusive, and normal aorta. J Vasc Surg 22: 295-305.
  34. Annabi B, Shédid D, Ghosn P, Kenigsberg RL, Desrosiers RR, et al. (2002) Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms. J Vasc Surg 35: 539-546.
  35. Carrell TW, Burnand KG, Wells GM, Clements JM, Smith A (2002) Stromelysin-1 (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase-3 are overexpressed in the wall of abdominal aortic aneurysms. Circulation 105: 477-482.
  36. Curci JA, Liao S, Huffman MD, Shapiro SD, Thompson RW (1998) Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J Clin Invest 102: 1900-1910.
  37. Will H, Atkinson SJ, Butler GS, Smith B, Murphy G (1996) The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. J Biol Chem 271: 17119-17123.
  38. Kandalam V, Basu R, Moore L, Fan D, Wang X, et al. (2011) Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation 124: 2094-2105.
  39. Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, et al. (1998) The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem 273: 871-880.
  40. Crowther M, Goodall S, Jones JL, Bell PR, Thompson MM (2000) Increased matrix metalloproteinase 2 expression in vascular smooth muscle cells cultured from abdominal aortic aneurysms. J Vasc Surg 32: 575-583.
  41. Anidjar S, Salzmann JL, Gentric D, Lagneau P, Camilleri JP, et al. (1990) Elastase-induced experimental aneurysms in rats. Circulation 82: 973-981.
  42. Daugherty A, Cassis LA (2004) Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 24: 429-434.
  43. Bi Y, Zhong H, Xu K, Ni Y, Qi X, et al. (2013) Performance of a modified rabbit model of abdominal aortic aneurysm induced by topical application of porcine elastase: 5-month follow-up study. Eur J Vasc Endovasc Surg 45: 145-152.
  44. Heckenkamp J, Luebke T, Theis T, Schumacher L, Gawenda M, et al. (2012) Effects of vascular photodynamic therapy in a newly adapted experimental rat aortic aneurysm model. Interact Cardiovasc Thorac Surg 15: 69-72.
  45. Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, et al. (2000) Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 105: 1641-1649.
  46. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, et al. (2002) Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110: 625-632.
  47. Daugherty A, Manning MW, Cassis LA (2000) Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 105: 1605-1612.
  48. Basu R, Fan D, Kandalam V, Lee J, Das SK, et al. (2012) Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II. J Biol Chem 287: 44083-44096.
  49. Bai L, Beckers L, Wijnands E, Lutgens SP, Herías MV, et al. (2010) Cathepsin K gene disruption does not affect murine aneurysm formation. Atherosclerosis 209: 96-103.
  50. Uchida HA, Poduri A, Subramanian V, Cassis LA, Daugherty A (2011) Urokinase-type plasminogen activator deficiency in bone marrow-derived cells augments rupture of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 31: 2845-2852.
  51. Cassis LA, Gupte M, Thayer S, Zhang X, Charnigo R, et al. (2009) ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice. Am J Physiol Heart Circ Physiol 296: H1660-1665.
  52. Van Lint P, Libert C (2006) Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev 17: 217-223.
  53. Cuadrado E, Ortega L, Hernández-Guillamon M, Penalba A, Fernández-Cadenas I, et al. (2008) Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. J Leukoc Biol 84: 207-214.
  54. Matsuda A, Itoh Y, Koshikawa N, Akizawa T, Yana I, et al. (2003) Clusterin, an abundant serum factor, is a possible negative regulator of MT6-MMP/MMP-25 produced by neutrophils. J Biol Chem 278: 36350-36357.
  55. Lambert JM, Lopez EF, Lindsey ML (2008) Macrophage roles following myocardial infarction. Int J Cardiol 130: 147-158.
  56. Ikonomidis JS, Barbour JR, Amani Z, Stroud RE, Herron AR, et al. (2005) Effects of deletion of the matrix metalloproteinase 9 gene on development of murine thoracic aortic aneurysms. Circulation 112: I242-248.
  57. Xiong W, Knispel R, MacTaggart J, Greiner TC, Weiss SJ, et al. (2009) Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo. J Biol Chem 284: 1765-1771.
  58. Silence J, Lupu F, Collen D, Lijnen HR (2001) Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol 21: 1440-1445.
  59. Eliason JL, Hannawa KK, Ailawadi G, Sinha I, Ford JW, et al. (2005) Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation. Circulation 112: 232-240.
  60. Longo GM, Buda SJ, Fiotta N, Xiong W, Griener T, et al. (2005) MMP-12 has a role in abdominal aortic aneurysms in mice. Surgery 137: 457-462.
  61. Shimizu K, Mitchell RN, Libby P (2006) Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 26: 987-994.
  62. Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, et al. (1999) Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 104: 1191-1197.
  63. Shi GP, Munger JS, Meara JP, Rich DH, Chapman HA (1992) Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J Biol Chem 267: 7258-7262.
  64. Sun J, Sukhova GK, Zhang J, Chen H, Sjöberg S, et al. (2012) Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol 32: 15-23.
  65. Subramanian V, Uchida HA, Ijaz T, Moorleghen JJ, Howatt DA, et al. (2012) Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice. J Cardiovasc Pharmacol 59: 66-76.
  66. Schulte S, Sun J, Libby P, Macfarlane L, Sun C, et al. (2010) Cystatin C deficiency promotes inflammation in angiotensin II-induced abdominal aortic aneurisms in atherosclerotic mice. Am J Pathol 177: 456-463.
  67. Furubayashi K, Takai S, Jin D, Miyazaki M, Katsumata T, et al. (2008) Chymase activates promatrix metalloproteinase-9 in human abdominal aortic aneurysm. Clin Chim Acta 388: 214-216.
  68. Sun J, Zhang J, Lindholt JS, Sukhova GK, Liu J, et al. (2009) Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation. Circulation 120: 973-982.
  69. Gong Y, Hart E, Shchurin A, Hoover-Plow J (2008) Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest 118: 3012-3024.
  70. Carmeliet P, Moons L, Lijnen R, Baes M, LemaÎtre V, et al. (1997) Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17: 439-444.
  71. Jin J, Arif B, Garcia-Fernandez F, Ennis TL, Davis EC, et al. (2012) Novel mechanism of aortic aneurysm development in mice associated with smoking and leukocytes. Arterioscler Thromb Vasc Biol 32: 2901-2909.
  72. Silence J, Collen D, Lijnen HR (2002) Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ Res 90: 897-903.
  73. Ikonomidis JS, Gibson WC, Butler JE, McClister DM, Sweterlitsch SE, et al. (2004) Effects of deletion of the tissue inhibitor of matrix metalloproteinases-1 gene on the progression of murine thoracic aortic aneurysms. Circulation 110: II268-273.
  74. Xiong W, Knispel R, Mactaggart J, Baxter BT (2006) Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation. J Vasc Surg 44: 1061-1066.
  75. Basu R, Lee J, Morton JS, Takawale A, Fan D, et al. (2013) TIMP3 is the primary TIMP to regulate agonist-induced vascular remodelling and hypertension. Cardiovasc Res 98: 360-371.
  76. Patel MI, Hardman DT, Fisher CM, Appleberg M (1995) Current views on the pathogenesis of abdominal aortic aneurysms. J Am Coll Surg 181: 371-382.
  77. Agmon Y, Khandheria BK, Meissner I, Schwartz GL, Sicks JD, et al. (2003) Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions in the population with implications for thoracic aortic aneurysm formation. J Am Coll Cardiol 42: 1076-1083.
  78. Johnsen SH, Forsdahl SH, Singh K, Jacobsen BK (2010) Atherosclerosis in abdominal aortic aneurysms: a causal event or a process running in parallel? The Tromsø study. Arterioscler Thromb Vasc Biol 30: 1263-1268.
  79. Forsdahl SH, Singh K, Solberg S, Jacobsen BK (2009) Risk factors for abdominal aortic aneurysms: a 7-year prospective study: the Tromsø Study, 1994-2001. Circulation 119: 2202-2208.
  80. Wang JA, Chen WA, Wang Y, Zhang S, Bi H, et al. (2011) Statins exert differential effects on angiotensin II-induced atherosclerosis, but no benefit for abdominal aortic aneurysms. Atherosclerosis 217: 90-96.
  81. Ferguson CD, Clancy P, Bourke B, Walker PJ, Dear A, et al. (2010) Association of statin prescription with small abdominal aortic aneurysm progression. Am Heart J 159: 307-313.
  82. Yoshimura K, Aoki H, Ikeda Y, Fujii K, Akiyama N, et al. (2005) Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med 11: 1330-1338.
  83. Golub LM, Lee HM, Lehrer G, Nemiroff A, McNamara TF, et al. (1983) Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res 18: 516-526.
  84. Kivelä-Rajamäki M, Maisi P, Srinivas R, Tervahartiala T, Teronen O, et al. (2003) Levels and molecular forms of MMP-7 (matrilysin-1) and MMP-8 (collagenase-2) in diseased human peri-implant sulcular fluid. J Periodontal Res 38: 583-590.
  85. Sapadin AN, Fleischmajer R (2006) Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 54: 258-265.
  86. Petrinec D, Liao S, Holmes DR, Reilly JM, Parks WC, et al. (1996) Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: preservation of aortic elastin associated with suppressed production of 92 kD gelatinase. J Vasc Surg 23: 336-346.
  87. Curci JA, Petrinec D, Liao S, Golub LM, Thompson RW (1998) Pharmacologic suppression of experimental abdominal aortic aneurysms: acomparison of doxycycline and four chemically modified tetracyclines. J Vasc Surg 28: 1082-1093.
  88. Sheth RA, Maricevich M, Mahmood U (2010) In vivo optical molecular imaging of matrix metalloproteinase activity in abdominal aortic aneurysms correlates with treatment effects on growth rate. Atherosclerosis 212: 181-187.
  89. Turner GH, Olzinski AR, Bernard RE, Aravindhan K, Karr HW, et al. (2008) In vivo serial assessment of aortic aneurysm formation in apolipoprotein E-deficient mice via MRI. Circ Cardiovasc Imaging 1: 220-226.
  90. Manning MW, Cassis LA, Daugherty A (2003) Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 23: 483-488.
  91. Xie X, Lu H, Moorleghen JJ, Howatt DA, Rateri DL, et al. (2012) Doxycycline does not influence established abdominal aortic aneurysms in angiotensin II-infused mice. PLoS One 7: e46411.
  92. Baxter BT, Pearce WH, Waltke EA, Littooy FN, Hallett JW Jr, et al. (2002) Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study. J Vasc Surg 36: 1-12.
  93. Lindeman JH, Abdul-Hussien H, van Bockel JH, Wolterbeek R, Kleemann R (2009) Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells. Circulation 119: 2209-2216.
  94. Hackmann AE, Rubin BG, Sanchez LA, Geraghty PA, Thompson RW, et al. (2008) A randomized, placebo-controlled trial of doxycycline after endoluminal aneurysm repair. J Vasc Surg 48: 519-526.
  95. Wang Y, Ait-Oufella H, Herbin O, Bonnin P, Ramkhelawon B, et al. (2010) TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest 120: 422-432.
  96. Lizarbe TR, Tarin C, Gomez M, Lavin B, Aracil E, Orte LM, et al. (2009) Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN. Am J Pathol 175: 1421-1430.
Citation: Basu R, Kassiri Z (2013) Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm. J Clin Exp Cardiolog 4:259.

Copyright: © 2013 Basu R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.