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Keywords:

  • Abdominal aortic aneurysm;
  • angiotensin-converting enzyme;
  • renin–angiotensin system

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Background

Abdominal aortic aneurysm (AAA) is a complex degenerative disease, which leads to morbidity and mortality in a large portion of the elderly population. Current treatment options for AAA are quite limited as there is no proven indication for pharmacological therapy and surgery is recommended for AAA larger than 5·5 cm in luminal diameter. Thus, there is a great need to elucidate the underlying pathophysiological cellular and molecular mechanisms to develop effective therapies. In this narrative review, we will discuss recent findings concerning some potential molecular and clinical aspects of the renin–angiotensin system (RAS) in AAA pathophysiology.

Materials and methods

This narrative review is based on the material found on MEDLINE and PubMed up to April 2013. We looked for the terms ‘angiotensin, AT1 receptor, ACE inhibitors’ in combination with ‘abdominal aortic aneurysm, pathophysiology, pathways’.

Results

Several basic research and clinical studies have recently investigated the role of the RAS in AAA. In particular, the subcutaneous infusion of Angiotensin II has been shown to induce AAA in Apo56 knockout mice. On the other hand, the pharmacological treatments targeting this system have been shown as beneficial in AAA patients.

Conclusions

Emerging evidence suggests that RAS may act as a molecular and therapeutic target for treating AAA. However, several issues on the role of RAS and the protective activities of angiotensin-converting enzyme (ACE) inhibitors and Angiotensin 1 receptors blockers against AAA require further clarifications.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Abdominal aortic aneurysm (AAA) is a degenerative and inflammatory disease in the aortic wall that affects a large portion of the elderly population and may lead to lethal complications [1]. Annually, AAA rupture causes nearly 15 000 deaths in the United States, corresponding to 1·3% of all deaths in the 65- to 85-year-old male population [2, 3]. Intriguingly, there is a higher prevalence of AAA in the male gender: approximately 5% of men over 60 years old are affected by AAA, while it affects only 1% of women within the same age range [4, 5]. Other risk factors for AAA include ageing, cigarette smoking, atherosclerosis, hypertension and genetic predisposition (up to 20% of AAA patients have one or more affected relatives) [1, 6-8].

The majority of aortic aneurysms occur in the abdominal region [8]. AAA is defined as a local expansion of the abdominal aorta wall, with at least a 50% increase above on its normal diameter [9]. This diameter enlargement is a result of a complex maladaptive vascular remodelling involving different integrated aspect. A detailed pathophysiological understanding of AAA is still incomplete, but it is clearly associated with alterations of the connective tissue in the aortic wall and smooth muscle cell depletion, which leads to a weakening of the wall strength and consecutive vessel dilatation [1, 10]. The initial stage is characterized by the fragmentation of elastic fibres, which is dependent on production of proteases by resident vascular wall cells and immune cells [2, 11]. In response to elastin degradation, as well as proinflammatory cytokines, there is an increased leucocyte infiltration. This local inflammation favours the intensification of proteolytic enzymes production, which is critical for the progression of extracellular matrix degradation [2]. Accompanying this event, a depletion of medial smooth muscle cells due to apoptosis makes an important contribution to the evolution of AAA degeneration [2, 10]. A chronic mural thrombus might also occur and further complicate the disease progression [2]. All these structural changes result in a collapse of the arterial wall integrity and rupture when the arterial wall is no longer able to withstand the internal blood pressure [1].

Currently, there are no clear recommendations on pharmacological treatment approaches to potentially prevent aneurysm progression or to reduce the risk of rupture [12, 13]. Open surgical repair and endovascular exclusion strategies are the only recommended treatments [13]. Surgery is recommended for AAAs when luminal diameter is larger than 5·5 cm [14, 15]. In the United States, nearly 25 000 aortic repairs are annually performed [3, 16]. This clinical impact strongly supports the relevance of cellular and molecular researches to develop novel effective therapies against AAA.

The renin–angiotensin system (RAS) is a peptidergic hormone system, which plays a central role in cardiovascular haemostasis [17]. This system may act through endocrine, paracrine or autocrine pathways, modulating numerous cell functions [18, 19]. Functional disturbances of the RAS are associated with many cardiovascular disorders, including a critical involvement in the pathogenesis and progression of AAA [20]. In fact, pharmacological therapeutics based on the inhibition of the angiotensin-converting enzyme (ACE) and on the blockade of AT1 receptors have been suggested as potential treatments to stabilize AAA, thus reducing the risk of rupture [21-24].

In this review, we will discuss recent findings concerning the pathophysiological role of the RAS on AAA. We will focus on the molecular pathways, histopathological changes and existing pharmacotherapies. Material searched was obtained via Medline/PubMed up to April 2013. Search terms used were ‘angiotensin, AT1 receptor, ACE inhibitors’ in combination with ‘abdominal aortic aneurysm, pathophysiology, pathways’.

RAS cascade

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

The RAS is a peptidergic hormone system, which has been recognized to be highly involved in disturbances of the cardiovascular system [25]. In addition, RAS has been indicated as an important target in the management of cardiovascular diseases (CVDs) [19, 26, 27]. In a classical view, the RAS is an endocrine system activated by the release of renin from the juxtaglomerular cells following a reduction in blood pressure [19]. In the systemic circulation, renin cleaves the zymogen angiotensinogen, which is synthetized and secreted principally by the liver. Angiotensinogen is thus converted into angiotensin (Ang) I. Ang I, a decapeptide void of known biological effects, is subsequently cleaved by ACE, an enzyme mainly expressed on the surface of vascular endothelial cells, forming the octapeptide Ang II, which is considered as a major effector of the RAS [19, 28]. Additionally, many alternative pathways of Ang II formation have been described [29-32]. One of the most relevant Ang II-forming enzymes, especially under vascular pathologies, is the chymase [32]. While ACE is mainly expressed in endothelial and smooth muscle cells or in infiltrated macrophages, chymase expression appears to be restricted to mast cells [33]. Importantly, evidences suggest that mast cell chymase is the primary source of Ang II increase in AAA [34].

Ang II is the endogenous agonist of two distinct G protein-coupled receptors: AT1 and AT2 receptors [19, 27, 35]. In both physiological or pathological conditions, AT1 activation is associated with an increase in blood pressure by stimulating vasoconstriction and sodium retention; furthermore, it produces proliferation, fibrosis and inflammation [19, 25]. The relevance of Ang II/AT1 actions was emphasized by the tremendous success of ACE inhibitors and AT1 receptors blockers (ARBs) and is considered as the main class of drugs for the treatment of hypertension and CVDs [25, 36].

Ang II may also activate the AT2 receptor, producing vasodilation, antiproliferative and anti-inflammatory actions, antagonizing the aforementioned AT1-mediated effects [37-39]. As the expression of AT1 receptor is much higher than AT2, actions resulting from AT1 receptor activation prevail when the Ang II levels are increased. A comprehensive understanding of the role of the AT2 receptor has, however, not yet been fully elucidated.

The discovery of the RAS begun over 100 years ago by Tigerstedt and Bergman [40], but its conception and complexity continues until today. The classical view of the RAS as a purely endocrinal system has expanded over the years [41, 42]. Many organs and tissues express the major components of the RAS, and evidence has suggested that RAS may also act in a paracrine manner [19]. Indeed, the existence of a local RAS in the heart, kidney, blood vessels and brain has been shown by numerous studies in animals and humans [19, 41]. Thus, the RAS may be locally autonomous and have important regulatory functions in a wide range of organs, as well as a relevant pathophysiological impact [41, 29]. Moreover, the classical view of sequential enzymatic reactions culminating in the generation and action of Ang II has expanded into a more multifaceted view [42]. In addition to Ang II, the RAS has been shown to include other biological effectors, including Ang III, Ang IV, Ang A and Ang-(1-7). These peptides are not well characterized as compared to Ang II, but they have been shown to play a functional physiological role [35, 43]. These peptides may have similar, additive or antagonistic effects as those elicited by Ang II [43, 44]. For instance, Ang III activates AT1 and AT2 receptors, producing similar effects to Ang II [43], whereas Ang IV acts through its binding to AT4 receptor, and its actions involve blood flow regulation, exploratory behaviour, learning and memory effects and neuronal development [43, 45]. Among the aforementioned angiotensin peptides, the heptapeptide Ang-(1-7) appears to be crucial in both physiological and pathophysiological conditions [42, 46]. This peptide is mainly formed when ACE2 cleaves the C-terminal phenylalanine of Ang II [47, 48]. Acting via its own receptor, Mas [49], Ang-(1-7) stimulates vasodilation [49-51], NO release [52] and antiproliferative [53], antifibrotic [54, 55] and anti-inflammatory [56] effects and is therefore considered to be the main endogenous counter-regulator of Ang II [41, 42, 57]. Indeed, a novel paradigm emerged where two major axes are now assumed to modulate the RAS function: one deleterious axis composed by ACE, Ang II and AT1 receptor, and another beneficial axis composed by ACE2, Ang-(1-7) and Mas receptor [46, 58, 59]. These newly discovered functional aspects of the RAS do not only expand our understanding of this complex system, but they also increase the range of possible targets for the treatment of CVDs.

Animal models of Ang II-induced AAA

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Evidence from basic research has indicated a critical role of the RAS in AAA pathogenesis. To understand the pathophysiological mechanisms underlying this complex disease, different animal models have been investigated. One of the most common AAA models is the subcutaneous infusion of Ang II into hypercholesterolaemic mice (e.g. LDL−/− or ApoE−/− fed with saturated fat-enriched diet) [20, 21, 60-63]. Ang II-induced AAA in ApoE−/− mice does not only underscore the critical role of the RAS in the pathogenesis of the disease, but it has also become a common approach to study the human disease pathophysiology [21].

Similar to human being, medial degradation and thrombus formation, as well as the activation of an inflammatory response that stimulates medial elastolysis, have been observed in mice. Another important characteristic that is in agreement with clinical observations is the influence of the gender: AAA prevalence in Ang II-infused ApoE−/− mice has a male gender preference [64]. Despite these similarities between human AAA and the mouse model of Ang II-induced AAA, there are also three major important differences. The first is the common occurrence of AAA in the renal region in humans compared to suprarenal region in mice [62]. Several different hypotheses have been proposed to explain this aspect: a hemodynamic difference between humans and mice potentially exists as the murine arteries experience much more laminar flow conditions and higher shear stresses than humans [65, 66] and the renal arteries branch off at asymmetric locations in mice [67]. Other possible explanations include the fact that the elastin to collagen ratio is minimal in the infrarenal aorta in humans [68, 69], and the suprarenal aorta of mice may be more susceptible for leucocyte infiltration when compared to the proximal and distal aorta. Leucocyte infiltration occurs in the early stage of AAA, due to the presence of a higher amount of unilocular white adipocytes in the adventitia [70]. This periaortic adipose tissue provides an abundant resource for leucocyte infiltration and proinflammatory cytokine secretion to the suprarenal aorta during Ang II infusion [64, 70]. The second major difference is that in the Ang II-induced AAA animal model, aneurysm formation is preceded by aortic dissection of the media and the aneurysm shape frequently takes a saccular form [62], while human AAA is usually fusiform. Finally, the third main difference is represented by the location of the thrombus. In human AAA, the thrombus is located in the aortic lumen [1, 2], while in the Ang II-induced AAA mouse model, it is located within the aortic wall [21, 64]. These differences should be taken in account when translating animal data to the human disease.

Understanding the risk factors involved in AAA is necessary to prepare a screening plan to prevent this disease. Several studies reveal that hyperlipidaemia and male gender are key factors for the development of AAA. Normocholesterolemic mice have a three- to fourfold lower incidence of AAA induced by Ang II when compared to hypercholesterolaemic mice [64, 71, 72]. In humans, however, the association between hypercholesterolaemia and AAA development is still unclear [13]. Although hyperlipidaemia is a relevant factor in the pathogenesis of AAA, Ang II infusion in mice has no direct effect on serum cholesterol or triglyceride profile [20, 61], indicating that the influence of Ang II is independent of lipid profile changes. Male gender is another risk factor which is pivotal in AAA. This is a consistent characterization, as a significantly higher prevalence of Ang II-induced AAA is observed in male when compared to female mice [73, 74].

Epidemiological data indicate that increased systolic pressure, which is a major risk factor for different CVDs, is not associated with AAA development; neither in humans [8, 75] nor in animal models [76]. Infusion of norepinephrine increased arterial blood pressure in ApoE−/− male mice without leading to AAA development [76]. Moreover, using a half dose of Ang II (500 ng/Kg/min) leads to AAA development without a significant change in the arterial blood pressure [76], suggesting that the effects of Ang II are independent of its pressure-increasing activity.

Molecular mechanisms of Ang II leading to AAA

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Cytokine secretion and inflammatory cells accumulation in the arterial wall may contribute to the development of AAA [77-82]. The initial stage of the Ang II-induced AAA mouse model is macrophage accumulation in the subintimal space during the first 2 days. The secretion of chemoattractants is responsible for the initiation of this process, and CCL2 appears to be an essential cytokine in this process [62, 77, 83]. This CC chemokine is mainly secreted by endothelial and vascular smooth muscle cells in response to Ang II stimulation [84, 85]. In addition to CCL2, CCL5 apparently plays a relevant role on Ang II-induced AAA. It is known that formation of CXCL4-CCL5 heterodimer considerably augments CCL5-mediated monocyte adhesion, arrest, and transmigration [86]. It was reported that pretreatment with MKEY, a synthetic cyclic peptide which prevents CXCL4–CCL5 heterodimer formation, significantly lowered AAA incidence, enlargement and mortality in the Ang II-infused ApoE−/− mouse model [86]. In another experimental AAA model by intra-aortic porcine pancreatic elastase infusion, MKEY pretreatment also reduced aortic diameter enlargement, preserved medial elastin fibres and smooth muscle cells and attenuated mural macrophage infiltration, angiogenesis, and aortic metalloproteinase 2 and 9 expression [86].

Different inflammatory pathways are involved in Ang II-induced AAA. It was shown that Ang II-induced AAA was attenuated in cyclooxygenase-2 (COX-2) deficient mice [87]. Supporting this finding, Ang II was demonstrated to augment the protein expression of COX-2 [88]. COX-2 is an enzyme that catalyses the conversion of arachidonic acid into vasoactive and inflammatory prostaglandins [89], serving as an important modulator in AAA pathogenesis. Additionally, inhibition of COX-2 attenuates the incidence and severity of AAA [72].

Osteopontin (OPN, a secreted protein implicated in bone tissue repair, remodelling and inflammation) [90-92], is also suggested to play an important role in the Ang II-induced AAA [93]. OPN, which is mainly derived from macrophages, monocytes and, to a lesser extent, endothelial and vascular smooth muscle cells, mediates important cell signalling pathways, modulating cell growth, migration, inflammation and tissue remodelling [91, 93]. In addition, OPN may act as a chemotactic cytokine, regulating immune cell function and promoting the adhesion, migration, and activation of macrophages [90]. It was shown that Ang II-induced AAA was reduced in mice double knockout for ApoE and OPN genes. Moreover, this effect was associated with a decrease in MMP-2 and MMP-9 activity and with macrophage accumulation [91, 93].

It is well known that the extracellular matrix plays an important role in maintaining vessel wall integrity [94]. The main components of the matrix are elastin and collagen, and the disruption of these components is critical in the pathogenesis of AAA. MMPs (especially MMP-2 and MMP-9) are the major gelatinases responsible for the degradation of extracellular matrix. It has been shown that one of the mechanisms by which Ang II induces AAA is through the augmented production and activity of these MMPs [94-97]. In fact, luminal dilatation occurs within 4–8 days in Ang II-induced AAA, due to elastin disruption and extracellular matrix degradation in the medial layer [62]. Expression levels of UPA/plasmin mRNA, an important activator of MMPs, increased 13 times in aneurysmatic tissue when compared to normal tissue [61]. It was observed that a broad-spectrum MMP inhibitor, doxycycline, significantly reduced the incidence and severity of Ang II-induced AAA formation [98]. Moreover, it was shown that in vivo MMP2 deficiency by siRNA delivery blocked Ang II-induced elastin degradation in hypercholesterolaemic ApoE−/− mice [99]. In this line, Yoshimura and coworkers have documented that JNK activity is crucial for secretion of macrophage-derived MMP-9 and interstitial cell-derived MMP-2. Moreover, inhibition of JNK resulted in a marked suppression of MMP activities, cellular infiltration and caused regression of Ang II-induced AAA already after being established [100]. Although these evidences suggest a role of MMPs in Ang II-induced AAAs, recent studies have failed to reproduce these data [101, 102]. In both independent studies, doxycycline did not influence Ang II-induced AAA [101, 102]. Additionally, other researchers observed that in an engineered mouse model resistant to collagenases, Ang II infusion enlarged and exacerbated AAA [103]. Hence, further studies are needed to clarify the controversial role of MMPs in Ang II-induced AAA.

Oxidative stress has also been shown to be an essential factor in AAA development. Reactive oxygen species (ROS), which are produced by many cell types such as inflammatory cells, endothelial, smooth muscles and fibroblasts [104], can regulate cell signalling pathways leading to cell growth and proliferation and are found in increased concentrations leading to organ damage [105, 106]. Several studies have shown that Ang II is a potent stimulator of ROS production, provoking numerous disorders, including AAA [107]. In AAA, Ang II-induced ROS leads to an increased inflammatory profile, MMP activation and smooth muscle cell apoptosis [108]. It was observed that vitamin E, an antioxidant agent, attenuated AAA formation induced by Ang II [107]. Moreover, Wang and colleagues [99] have demonstrated that Ang II-derived ROS trigger nuclear translocation of the AMP-activated protein kinase alpha2 (a serine/threonine kinase essential in energy homeostasis), resulting in aberrant expression of MMP2, extracellular matrix degradation and consequent AAA formation. Other researchers have reported that cyclophilin A (a proinflammatory chaperone protein abundantly expressed in vascular smooth muscle cells secreted in response to ROS) is crucial in the development of Ang II-induced AAA in mice. Cyclophilin A deletion completely protected against AAA formation in ApoE−/− mice infused with Ang II, while its overexpression in vascular smooth muscle cells enhanced AAA formation [109].

Overall, the Ang II-induced AAA mouse model is a widely used approach to address the pathophysiological mechanism of this disease. Existing evidence indicates that the mechanism by which Ang II induces AAA is independent of systolic blood pressure increase and serum lipid profile changes, but involves inflammatory cell infiltration and extracellular matrix disruption.

RAS and the treatment of AAA

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Several therapeutic breakthroughs have been achieved through pharmacologically targeting the RAS. Indeed, the relevance of the RAS was emphasized by the remarkable success of therapeutics based on the pharmacological inhibition of ACE and the blockade of the AT1 receptor [36, 110]. In general, these drugs (ACEi and ARBs) not only decrease arterial pressure, but also prevent or reverse endothelial dysfunction and atherosclerosis, which results in a reduction in cardiovascular mortality and morbidity [25]. Additionally, evidence indicates that these drugs have a beneficial effect in AAA [101, 111, 112] independently of their antihypertensive effect, as other antihypertensive agents [such as propranolol and hydralazine (a β-receptor antagonist and a diuretic, respectively)] decreased blood pressure without affecting AAA development [76, 113]. Daugherty and colleagues [22] showed that treatment with Losartan completely prevents AAA development induced by Ang II. On the other hand, other researchers documented that both ARB and ACEi (Candesartan and Lisinopril, respectively) blocked the AAA progression in Ang II-induced AAA in ApoE−/− mice [111]. Importantly, evidence addressing the effectiveness of RAS blockers against AAA is not limited to Ang II-induced aneurysms models. In a murine AAA model, in which aortic aneurysmal degeneration is initiated via intra-aortic infusion of porcine pancreatic elastase in normolipidemic C57BL/6J mice, without exposure to exogenous Ang II, Iida and colleagues [101] observed that telmisartan was also highly effective and almost completely abolished AAA degeneration. Similar data were obtained by other researchers using another ARB, valsartan [24]. These results indicate that the potent inhibitory effect of ARB treatment in AAA is independent of the mouse experimental model. Similarly, ACEi might also prevent induction of AAA independently of Ang II infusion. Liao and coworkers have documented that, in an elastase-perfused AAA model in rats, ACEi reduced elastin degradation and decreased the AAA diameter, while ARBs were ineffective [23]. This absence of response to ARBs is in accordance with a large population-based case–control study by Hackman and colleagues, demonstrating that only ACEi (but not ARBs) reduce the risk of rupture in AAA [113]. It is important to note that in this study the number of subjects using ARBs was smaller than other groups (1% of the whole cohort) [113].

The protective actions of ARBs against AAA and the potent inducing effect of Ang II point out a crucial role of the AT1 receptor in this pathology. This receptor is expressed as two structurally similar subtypes AT1a and AT1b. Although these two receptors are highly homologous and cannot be discriminated by ARBs, they have distinct patterns of distributional and functional characteristics. The AT1a isoform appears to be the primary regulator of most Ang II actions [114]. Cassis and coworkers [115] have documented that Ang II-induced AAA was absent in hypercholesterolaemic mice genetically-deleted for AT1a receptor. Differently, it was reported that AT1b receptor gene deletion had no effect on aneurysms of either ascending or abdominal aorta regions [116]. These studies suggest an essential role of the AT1a receptor subtype, but not AT1b. Further, efforts were done to explore the potential cell subsets involved in the action of Ang II to induce AAA via AT1a. Using a bone marrow transplantation chimera model, Cassis and coworkers observed that AT1a receptors expressed on infiltrating cells did not influence Ang II-induced AAA [115]. Surprisingly, using a model of cell-specific AT1a receptor deficiency [114], the same group reported that AT1a receptors depletion in either endothelial or smooth muscle cells did not affect either atherosclerosis or AAA. Therefore, additional studies are needed to clarify the relative role of AT1a receptors on specific cell types in AAA formation.

Despite of its action via AT1 receptor, Ang II also activates AT2 receptor. However, AT2 activation often produces opposite effects from AT1 [117]. Therefore, it has been postulated that selective AT2 stimulation would protects against AAA. If fact, it was observed, in a mouse model of Ang II-induced AAA, that coinfusion of Ang II and PD123319 (an AT2 receptor antagonist) significantly increased the incidence of severe AAA, suggesting a protective action of AT2 receptor [22]. In this line, others have documented that AT2 deletion accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome [118]; moreover, the same study suggested that AT2 activation protects against aneurysm through attenuation of ERK phosphorylation. Contrarily to these studies, it has been documented that PD123319 augments Ang II-induced AAA through an AT2 receptor-independent mechanism [119]. Therefore, the role of AT2 receptor on AAA still needs to be elucidated.

In summary, we might conclude that the existing evidence in literature suggests that both ACEi and ARBs are likely to have a protective effect against AAA (relevant preclinical studies addressing the effects of ACEi and ARBs are summarized in Table 1) [22-24, 101, 111, 112, 118, 120-122]. However, clinical trials are needed to establish this concept and make the step towards clinical application.

Table 1. Relevant preclinical studies investigating the effects of angiotensin-converting enzyme inhibitors (ACEi) and AT1 receptors blockers (ARBs) in abdominal aortic aneurysm (AAA) models
StudyDrugEffectExperimental modelComments
  1. +, Effective; ++, Intensively effective; −, Ineffective.

  2. a

    Dose in drinking water, which lead a daily intake of 4–6 mg/kg for each compound.

  3. b

    In drinkable water.

Daugherty et al. [22]Losartan (30 mg/kg/day)++Ang II subcutaneous infusion (1 μg/kg/min) in female ApoE−/− miceLosartan completely prevent AAA induced by Ang II
Inoue et al. [111]Candesartan (30 mg/kg/day)++Ang II subcutaneous infusion (1 μg/kg/min) in male ApoE−/− miceTreatments were initiated after 28 days of Ang II infusion and lasted for 20 weeks. Both ACEi and ARB blocked the AAA progression
Lisinopril (60 mg/kg/day)++
Fujiwara et al. [24]Valsartan (1 mg/kg/day)+Transient intra-aortic porcine pancreatic elastase infusion in male Wistar ratAAA model independent of exogenous Ang II administration
Iida et al. [101]Telmisartan (30 mg/kg/day)++Ang II subcutaneous infusion (1 μg/kg/min) in male ApoE−/− mice; and, transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 miceBoth treatments were initiated 1 week prior to AAA induction and lasted for 28 days (preventive study); In the same study, doxycycline, fluvastatin and bosentan did not influence aneurysm progression; Irbesartan and Telmisartan were effective in both experimental models
Irbesartan (50 mg/kg/day)++
Liao et al. [23]Captopril (250 mg/L)a+Transient intra-aortic porcine pancreatic elastase infusion in male Wistar ratsACE inhibitors were effective in the prevention of AAA, while the AT1 inhibitor was ineffective;
Enalapril (250 mg/L)a++
Lisinopril (250 mg/L)a++
Losartan (250 mg/L)a
Alsac et al. [112]Perindopril (3 mg/kg/day)+Decellularized aortic xenotransplants (from male guinea pigs) in Lewis ratAnimal model distant of human pathology
Kanematsu et al. [120]Captopril (6 mg/kg/day)DOCA-salt model associated to degeneration of elastic lamina by β-aminopropionitrile infusion in male C57BL/6 miceModel of thoracic and abdominal aneurysm; Captopril treatment did not decrease the blood pressure
Habashi et al. [121]Losartan (0·6 g/L)b+Mouse model of Marfan syndrome-associated AAAIt was used a transgenic mouse model, and the limitation of that should be taken in account
Habashi et al. [118]Enalapril (10–15 mg/Kg/day)Mouse model of Marfan syndrome-associated AAAIt was used a transgenic mouse model, and the limitation of that should be taken in account
Losartan (40–60 mg/Kg/day)+
Kaschina et al. [122]Telmisartan (0·5 mg/kg/day)+Transient intra-aortic porcine pancreatic elastase infusion in male Wistar ratsAAA model independent of exogenous Ang II administration

Future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Overall, the discussion above supports the concept that the RAS is critically involved in the pathogenesis of AAA. Moreover, pharmacological therapies targeting this system have been beneficial in AAA patients. However, several underlying issues regarding the role of RAS on AAA and beneficial actions of ACEi and ARBs against AAA still need to be clarified. Therefore, several areas of research should be investigated:

  1. Limited and contradictory data regarding the beneficial effects of ACEi and ARBs in human AAA exist, and therefore, future clinical trials are needed;
  2. Several studies showed that Ang II induces AAA by increasing the inflammatory profile; however, its molecular pathway is still poorly understood. Thus, new studies addressing the inflammatory pathogenesis of Ang II inducing AAA are crucial to better understand this disease;
  3. Few preliminary studies investigated the potential protective action of AT2 receptor against AAA [22, 119]. Additional studies are needed to establish the action of AT2 against AAA, clarify the molecular pathways and evaluate the efficacy of selective AT2 agonists;
  4. Emerging evidence has shown that the RAS is a complex system involving many effectors; however, most of them are less characterized than Ang II. Thus, it is necessary to evaluate the effects of the other RAS members on the development of AAA.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Growing evidence indicates that the RAS plays a critical role on the pathogenesis of AAA, and it is a potential target for the treatment of this disease. However, clinical trials and studies addressing the mechanisms of action of ACEi and ARBs are needed to consider these treatments in clinical practice.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

This research was funded by EU FP7, Grant number 201668, AtheroRemo to Dr F. Mach. This study was supported by European Commission (FP7-INNOVATION I HEALTH-F2-2013-602114; Athero-B-Cell: Targeting and exploiting B-cell function for treatment in cardiovascular disease). This work was supported by Swiss National Science Foundation Grants to Dr F. Montecucco (#32003B_134963/1) and to Prof. F. Mach (#310030_118245). This study was supported by grants from the Norvatis Foundation and the Foundation ‘Gustave and Simone Prévot’ to Dr F. Montecucco.

Address

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References

Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Station 17, BM 5125, CH-1007, Lausanne, Switzerland (S. Malekzadeh, R. A. Fraga-Silva, B. Trachet, N. Stergiopulos); IBITech-bioMMeda, Ghent University, De Pintelaan 185B, 9000 Gent, Belgium (B. Trachet); Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland (F. Montecucco, F. Mach); First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, 6 viale Benedetto XV, 16100 Genoa, Italy (F. Montecucco); IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16100 Genoa, Italy (F. Montecucco); Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland (F. Montecucco).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. RAS cascade
  5. Animal models of Ang II-induced AAA
  6. Molecular mechanisms of Ang II leading to AAA
  7. RAS and the treatment of AAA
  8. Future directions
  9. Conclusions
  10. Acknowledgements
  11. Conflict of interest
  12. Address
  13. References