Is There a New Target in the Renin–Angiotensin System for Aortic Aneurysm Therapy?

Abstract

A ortic aneurysm and aortic dissection are important causes of mortality, which are principally managed by surgical interventions.1-3 The absence of specific medications which can limit the complications of these important aortic pathologies has stimulated an intense interest in studying the mechanisms underlying these diseases.1-3 A major focus of these studies has been the renin-angiotensin system. Angiotensin II has been linked to aortic aneurysm and dissection on the basis of evidence from a range of studies. In >100 studies in specific mice species (eg, apolipoprotein E-deficient mice), it has been shown that angiotensin II infusion stimulates aortic aneurysm and dissection formation and rupture.1 Such angiotensin II-induced aneurysms have some features typically found in human abdominal aortic aneurysms, including upregulation of proinflammatory cytokines and matrix metalloproteinases and marked influx of inflammatory cells. 4 The concentration of a variety of angiotensin II-producing enzymes, including angiotensin-converting enzyme (ACE) and chymase, is increased in biopsies of human aortic aneurysm. 5 In some rodent model studies inhibiting angiotensin II using angiotensin type 1 receptor (ATR1) blockers or ACE inhibitors has been successful in limiting aneurysm development or progression.1,3 Genetic polymorphisms in the ATR1 have been associated with human aortic aneurysm.6 On the basis of these and other data, several trials are underway to assess the efficacy of ATR1 blockers and ACE inhibitors in limiting progression of thoracic and abdominal aortic aneurysm. 3 See accompanying article on page 1568One of the many effects of angiotensin II is to stimulate release of the mineralocorticoid aldosterone from the adrenal cortex. In the current issue of Arteriosclerosis, Thrombosis and Vascular Biology, Liu et al 7 describe studies investigating the role of the mineralocorticoid receptor (MR) in aortic aneurysm and dissection development in C57BL/6 male mice. There were 4 key findings of the study. First, administration of a MR agonist plus salt induced aortic aneurysm and dissection. Second, the aneurysms had some histological features similar to human aortic aneurysm, including elastin degradation, elevated matrix metalloproteinases activity, vascular smooth muscle cell apoptosis, macrophage and neutrophil infiltration, and upregulation of a range of inflammatory and oxidative stress markers. Histological evidence of aortic dissection was also demonstrated in 40% of the mice. Third, MR antagonism attenuated MR agonist and salt-induced aneurysm formation. Fourth, there was no association between the rise in blood pressure induced by MR and salt and the size or incidence of aneurysm development. Administration of an ATR1 blocker or ACE inhibitor did not influence aneurysm incidence despite lowering of blood pressure.Previously published data also support the role of the MR in aneurysm formation. Kanematsu et al 8 reported that administration of the MR agonist deoxycorticosterone acetate plus 1% salt (or ang...

Reported High Salt Intake Is Associated with Increased Prevalence of Abdominal Aortic Aneurysm and Larger Aortic Diameter in Older Men

“…Histological evidence of aortic dissection was also demonstrated in 40% of the mice. While aneurysm induction was associated with hypertension, the rise in blood pressure induced was not correlated with the size or incidence of aneurysm development [10], [19]. Our study provides the first evidence in older men, who are most at risk of AAA, that, similar to rodents, salt intake is associated with AAA.…”

“…The common feature of all these rodent model studies appears to be the administration of salt along with activation of a part of the renin-angiotensin-aldosterone system [19]. Raised blood pressure is another common feature of these models however lowering blood pressure does not necessarily inhibit aneurysm formation [10], [11], [19]. These findings are in keeping with our observation that higher salt intake was associated with AAA independently of a history of hypertension or treatment for hypertension and measured mean blood pressure.…”

Abdominal aortic aneurysm

“…Furthermore, Liu et al . [49] demonstrated that aldosterone can provoke aneurysm formation independently of AngII related mechanisms [49,50]. …”

Sex differences in abdominal aortic aneurysms

“…Multiple studies have indicated that the RAAS contributes to human AAA pathogenesis, as the enzymes involved in ANG II formation are upregulated in human AAA tissue (25,62,137,178). Furthermore, the RAAS is involved in vascular remodeling and inflammation seen in animal models of AAA pathogenesis (25,56). Thus, many in vivo studies have implemented chronic infusion of ANG II in ApoE Ϫ/Ϫ mice to model human AAA pathology (23,24,158).…”