Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

Abstract

BackgroundDespite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease.Methodology/Principal FindingsAAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion.Conclusion/SignificanceTelmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.

Angiotensin-Converting Enzyme 2 Decreases Formation and Severity of Angiotensin II–Induced Abdominal Aortic Aneurysms

“…Recent results demonstrate that blockade of AT1 receptors provides benefit against elastase-induced AAA formation. 11 Moreover, whole body AT1a receptor deficiency totally abolished AngII-induced AAAs, 10 demonstrating a critical role for AngII effects at AT1 receptors in both of these experimental AAA models. If ACE2 deficiency augmented AngII-induced AAAs by elevating AngII concentrations available to act at AT1 receptors, then we would have anticipated that ACE2 deficiency would have similar effects in both experimental AAA models (similar to AT1 receptor blockade).…”

“…Recent studies demonstrate that inhibition of the RAS also suppressed experimental aneurysms in an elastase-induced model. 11 Currently, it is unclear whether manipulation of the RAS is an effective mode for AAA therapy in humans. 12–16 However, several ongoing clinical trials (NCT01118520, NCT001904981) are either actively recruiting or in the process of evaluating efficacy of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists on either the size or expansion rate of human AAAs.…”

Many Faces of Matrix Metalloproteinases in Aortic Aneurysms

“…Administration of doxycycline, a nonspecific MMP inhibitor, to mice either reduced 16 or had no effects on AngII-induced AAA. 17 A prospective clinical trial has also reported that doxycycline has no beneficial effects on the growth of AAA. 18 Shen et al 9 propose another mechanism that AngII-induced TAA augmented by MMP-2 deficiency was associated with suppression of transforming growth factor (TGF)-β. TGF-β1 increased in the aorta in response to AngII, which was suppressed by MMP-2 deficiency (Figure).…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Nevertheless, the beneficial effects of these drugs against dissecting AAA were not restricted to the Ang II-induced model. ARBs and ACEi significantly ameliorated AAA in different animal models, including AAA-induction by intra-aortic infusion of porcine pancreatic elastase and in a DOCA-salt model associated to degeneration of elastic lamina by b-aminopropionitrile infusion, both of which are AAA models independent of Ang II infusion [33][34][35][36].…”

“…It has been shown that chemically modified tetracyclines without antibiotic activity exhibited similar efficacy to that of doxycycline by inhibiting AAA growth and disrupting the medial elastin in a rat model of AAA, induced by elastase perfusion [74]. Contradictory to these studies, Lida et al reported that doxycycline does not influence aneurysm progression in two different AAA animal models, Ang II-infused ApoE -/-mice or transient intra-aortic porcine pancreatic elastase infusion in B6 mice [33]. Similarly, Xie showed that doxycycline did not affect dissecting AAA progression and aortic rupture in Ang II-infused mice [75].…”