Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome

Abstract

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.MFS is a systemic disorder of connective tissue caused by mutations in FBN1, the gene encoding fibrillin-1 (1). As a principal component of the extracellular matrix microfibril (2, 3), fibrillin-1 was initially thought to play primarily a structural role in connective tissue. Several lines of evidence support an additional role as a regulator of the cytokine TGF-β (4, 5). Mice homozygous for a hypomorphic Fbn1 allele have impaired pulmonary alveolar septation associated with increased TGF-β signaling that can be prevented by perinatal administration of a polyclonal TGF-β neutralizing antibody (NAb) (5). Similarly, myxomatous

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary

“…In addition, biochemical abnormalities involved in the progression of aortic disease are being identified through studies of patients' aortic samples and animal models of the disease. 5,6 The biochemical alterations identified in the aortic tissue have the potential to serve as biomarkers for aortic disease. Understanding the molecular pathogenesis may lead to targeted therapy to prevent aortic disease.…”

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

“…Much remains unknown about ATAA pathology, largely because of the wide heterogeneity underlying these abnormalities. Nevertheless, most aortic aneurysms are associated with augmented angiotensin II (AngII) activity,6, 7, 8 and AngII‐infusion murine models have been established for both ATAA and abdominal aortic aneurysm (AAA) 9, 10, 11…”

A novel mutation of the fibrillin-1 gene in a newborn with severe Marfan syndrome

“…At 6 weeks, she was switched to losartan, an angiotensin II type I receptor blocker that has potential role in the treatment of Marfan's syndrome. 1 The losartan dose was titrated for blood pressure response (final dose 1.6 mg kg À1 per day) without adverse effects. However, mitral valve regurgitation progressed rapidly and a cardiac magnetic resonance imaging demonstrated massive dilation of the left atrium interfering with ventilation.…”

“…11 The antihypertensive agent losartan, an angiotensin II type 1 receptor blocker, which also antagonizes TGF-b signaling, has been shown to be effective in normalizing aortic root dimensions in FBN1 deficient animals when treated postnatally at a young age. 1 Its effect on the atrioventricular valve phenotype has not been tested yet, but based on the shared pathogenetic mechanism, it is a promising treatment for this severe and early lethal manifestation of nMFS. We treated our patient with losartan and the medication was well tolerated without adverse effects.…”