title: Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism.
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.
authors.affiliation: Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Habashi
authors.forename: Jefferson J
authors.initials: JJ
authors.lastname: Doyle
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Holm
authors.forename: Hamza
authors.initials: H
authors.lastname: Aziz
authors.forename: Florian
authors.initials: F
authors.lastname: Schoenhoff
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: YiChun
authors.initials: Y
authors.lastname: Chen
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Modiri
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta; D001014:Aortic Aneurysm / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001019:Aortic Rupture / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D020935:MAP Kinase Signaling System; D008382:Marfan Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D044139:Receptor, Angiotensin, Type 2; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D004656:Enalapril; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan