Angiotensin II Type 2 Receptor Signaling Attenuates Aortic Aneurysm in Mice Through ERK Antagonism

Jennifer P. Habashi,^1,2,* Jefferson J. Doyle,^1,* Tammy M. Holm,¹ Hamza Aziz,¹ Florian Schoenhoff,¹ Djahida Bedja,³ YiChun Chen,¹ Alexandra N. Modiri,¹ Daniel P. Judge,⁴ Harry C. Dietz^1,2,4,

Abstract: 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.

¹ Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

To whom correspondence should be addressed. E-mail: hdietz{at}jhmi.edu

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