Journal Article

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

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

2011

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: aneurysm / Aneurysms / angiotensin II / Angiotensin II - metabolism / Angiotensin II Type 1 Receptor Blockers - pharmacology / Angiotensin II Type 1 Receptor Blockers - therapeutic use / angiotensin-converting enzyme inhibitors / Angiotensin-Converting Enzyme Inhibitors - pharmacology / Angiotensin-Converting Enzyme Inhibitors - therapeutic use / animal models / Animals / Aorta / Aortic aneurysm / Aortic Aneurysm - drug therapy / Aortic Aneurysm - metabolism / Aortic Aneurysm - pathology / Aortic Aneurysm - prevention & control / Aortic Rupture - metabolism / Aortic Rupture - pathology / Aortic Rupture - prevention & control / Attenuation / Biological and medical sciences / Blocking / Blood and lymphatic vessels / Cardiology. Vascular system / Cellular biology / Connective tissues / Coronary vessels / Disease Models, Animal / Disease Progression / Diseases of the aorta / drugs / Enalapril - pharmacology / Enalapril - therapeutic use / Enzyme inhibitors / Inhibitors / Kinases / Losartan - pharmacology / Losartan - therapeutic use / MAP Kinase Signaling System / Marfan syndrome / Marfan Syndrome - drug therapy / Marfan Syndrome - metabolism / Marfan Syndrome - pathology / Medical sciences / Medical treatment / Mice / Mice, Knockout / mitogen-activated protein kinase / Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors / Mitogen-Activated Protein Kinase 3 - metabolism / Narcotics / Peptides / Placebos / Progressions / Receptor, Angiotensin, Type 2 - genetics / Receptor, Angiotensin, Type 2 - metabolism / Receptors / Rodents / Root growth / Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis / Signal Transduction / transforming growth factor beta / Transforming Growth Factor beta - metabolism