Abstract 4521: AT2 Signaling is a Positive Prognostic and Therapeutic Modifier of Marfan Syndrome: Lessons on the Inequality of ACEi and ARBs

Abstract

Marfan syndrome(MFS), a disorder that includes aortic aneurysm, is caused by mutations in the fibrillin-1 gene(FBN1). Murine models demonstrated that excess TGFβ signaling causes many manifestations of MFS including aortic aneurysm, which can be attenuated by antagonizing TGFβ with neutralizing antibody or the AngII type 1(AT1) receptor blocker losartan. TGFβ can signal through canonical (pSmad2/3) and noncanonical (MAPK, e.g. pERK1/2) cascades and their relative contribution to MFS has not previously been elucidated. We show that both pathways are activated in the ascending aorta in a mouse model of MFS(Fbn1+/−). Signaling of AngII through AT1 increases the expression of TGFβ ligands, receptors and activators, while signaling through AT2 is thought to antagonize these events in some cell types. Induction of AT2 signaling by AT1 blockade may contribute to the protective effect of losartan. AT2 signaling can also induce apoptosis, leading to the proposal that the dual AT1/AT2 blockade via ACEi is preferable. To address this, we disrupted the Agtr2 gene (encoding AT2;AT2KO) in Fbn1+/− mice. AT2KO:Fbn1+/− mice showed larger aortic dimensions by echocardiography than Fbn1+/− mice at 8 weeks (p<0.001), and this difference was maintained until sacrifice at 1 year of age. AT2KO:Fbn1+/− mice had worse aortic wall architecture, increased wall thickness and reduced elastic fiber content compared to Fbn1+/− alone (p<0.001, 0.01 and 0.001), while mice that lacked the AT2 receptor were identical to WT mice. pERK1/2 was further elevated in the AT2KO:Fbn1+/− mice, and the ERK antagonist U0126 reduced aortic growth in Fbn1+/− animals, suggesting that AT2 signaling is protective through inhibition of ERK signaling. Activation of ERK is both TGFβ and AT1 dependent. Losartan abolished ERK activation and prevented aneurysm progression (p<0.000001) while the ACEi enalapril which had no effect on ERK, did not decrease aortic growth (p=0.06). Losartan’s protection was lost in the AT2KO:Fbn1+/− mice (p<0.0001). AT2 signaling protectively modifies MFS and the selective AT1 antagonist losartan results in a superior clinical outcome. These data implicate MAPK and AT2 signaling in the pathogenesis of aortic aneurysm and identify potential therapeutic targets.