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

Overview

Journal Science

Specialty Science

Date 2006 Apr 8

PMID 16601194

Citations 696

Authors

Jennifer P Habashi

Daniel P Judge

Tammy M Holm

Ronald D Cohn

Bart L Loeys

Timothy K Cooper

Loretha Myers

Erin C Klein

Guosheng Liu

Carla Calvi

Megan Podowski

Enid R Neptune

Marc K Halushka

Djahida Bedja

Kathleen Gabrielson

Daniel B Rifkin

Luca Carta

Francesco Ramirez

David L Huso

Harry C Dietz

Affiliations

Soon will be listed here.

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-beta (TGF-beta) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-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.

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References

Jones K, Myers L, Judge D, Kirby P, Dietz H, Sponseller P . Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome. Spine (Phila Pa 1976). 2005; 30(3):291-3. DOI: 10.1097/01.brs.0000152166.88174.1c. View

Sakai L, Keene D, Glanville R, Bachinger H . Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J Biol Chem. 1991; 266(22):14763-70. View

Wolf G, Ziyadeh F, Stahl R . Angiotensin II stimulates expression of transforming growth factor beta receptor type II in cultured mouse proximal tubular cells. J Mol Med (Berl). 1999; 77(7):556-64. DOI: 10.1007/s001099900028. View

Schlumberger W, Thie M, Rauterberg J, Robenek H . Collagen synthesis in cultured aortic smooth muscle cells. Modulation by collagen lattice culture, transforming growth factor-beta 1, and epidermal growth factor. Arterioscler Thromb. 1991; 11(6):1660-6. DOI: 10.1161/01.atv.11.6.1660. View

Shores J, Berger K, Murphy E, Pyeritz R . Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med. 1994; 330(19):1335-41. DOI: 10.1056/NEJM199405123301902. View

Nagashima H, Sakomura Y, Aoka Y, Uto K, Kameyama Ki , Ogawa M . Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan's syndrome. Circulation. 2001; 104(12 Suppl 1):I282-7. DOI: 10.1161/hc37t1.094856. View

Dietz H, Cutting G, Pyeritz R, Maslen C, Sakai L, Corson G . Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991; 352(6333):337-9. DOI: 10.1038/352337a0. View

Heldin C, Miyazono K, Ten Dijke P . TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997; 390(6659):465-71. DOI: 10.1038/37284. View

Nabel E, Shum L, Pompili V, Yang Z, San H, Shu H . Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci U S A. 1993; 90(22):10759-63. PMC: 47857. DOI: 10.1073/pnas.90.22.10759. View

10.

Spence S, ALLEN H, Cukierski M, Manson J, Robertson R, Eydelloth R . Defining the susceptible period of developmental toxicity for the AT1-selective angiotensin II receptor antagonist losartan in rats. Teratology. 1995; 51(6):367-82. DOI: 10.1002/tera.1420510603. View

11.

Everett A, Fisher A, Gomez R . Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-beta 1 expression. Hypertension. 1994; 23(5):587-92. DOI: 10.1161/01.hyp.23.5.587. View

12.

Gadson Jr P, Dalton M, Patterson E, Svoboda D, Hutchinson L, Schram D . Differential response of mesoderm- and neural crest-derived smooth muscle to TGF-beta1: regulation of c-myb and alpha1 (I) procollagen genes. Exp Cell Res. 1997; 230(2):169-80. DOI: 10.1006/excr.1996.3398. View

13.

Lavoie P, Robitaille G, Agharazii M, Ledbetter S, Lebel M, Lariviere R . Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats. J Hypertens. 2005; 23(10):1895-903. DOI: 10.1097/01.hjh.0000182521.44440.c5. View

14.

Nollen G, van Schijndel K, Timmermans J, Groenink M, Barentsz J, van der Wall E . Pulmonary artery root dilatation in Marfan syndrome: quantitative assessment of an unknown criterion. Heart. 2002; 87(5):470-1. PMC: 1767105. DOI: 10.1136/heart.87.5.470. View

15.

Visconti R, Barth J, Keeley F, Little C . Codistribution analysis of elastin and related fibrillar proteins in early vertebrate development. Matrix Biol. 2003; 22(2):109-21. DOI: 10.1016/s0945-053x(03)00014-3. View

16.

Suzuki J, Iwai M, Nakagami H, Wu L, Chen R, Sugaya T . Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation. Circulation. 2002; 106(7):847-53. DOI: 10.1161/01.cir.0000024103.04821.86. View

17.

Daugherty A, Manning M, Cassis L . Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br J Pharmacol. 2001; 134(4):865-70. PMC: 1573019. DOI: 10.1038/sj.bjp.0704331. View

18.

Judge D, Biery N, Keene D, Geubtner J, Myers L, Huso D . Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest. 2004; 114(2):172-81. PMC: 449744. DOI: 10.1172/JCI20641. View

19.

Neptune E, Frischmeyer P, Arking D, Myers L, Bunton T, Gayraud B . Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003; 33(3):407-11. DOI: 10.1038/ng1116. View

20.

Ng C, Cheng A, Myers L, Martinez-Murillo F, Jie C, Bedja D . TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004; 114(11):1586-92. PMC: 529498. DOI: 10.1172/JCI22715. View