Losartan abrogated aortic aneurysm progression in a mouse model of Marfan syndrome by allowing continued protective AT2 signaling, which uniquely inhibited TGFβ-mediated activation of ERK.
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.
Habashi et al. (Thu,) conducted a other in Marfan syndrome (aortic aneurysm). Losartan vs. Enalapril was evaluated on Aneurysm progression. Losartan abrogated aortic aneurysm progression in a mouse model of Marfan syndrome by allowing continued protective AT2 signaling, which uniquely inhibited TGFβ-mediated activation of ERK.