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

American Association for the Advancement of Science (AAAS) - Tập 312 Số 5770 - Trang 117-121 - 2006
Jennifer Habashi1,2,3,4,5, Daniel P. Judge1,2,3,4,5, Tammy M. Holm1,2,3,4,5, Ronald D. Cohn1,2,3,4,5, Bart Loeys1,2,3,4,5, Timothy K. Cooper1,2,3,4,5, Loretha Myers1,2,3,4,5, Erin C. Steinbach1,2,3,4,5, Guosheng Liu1,2,3,4,5, Carla L. Calvi1,2,3,4,5, Megan Podowski1,2,3,4,5, Enid Neptune1,2,3,4,5, Marc K. Halushka1,2,3,4,5, Djahida Bedja1,2,3,4,5, Kathleen Gabrielson1,2,3,4,5, Daniel B. Rifkin1,2,3,4,5, Luca Carta1,2,3,4,5, Francesco Ramirez1,2,3,4,5, David L. Huso1,2,3,4,5, Harry C. Dietz1,2,3,4,5
1Department of Medicine Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
2Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4Departments of Cell Biology and Medicine, New York University School of Medicine, New York, NY 10016, USA.
5Howard Hughes Medical Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

10.1038/352337a0

10.1016/S0021-9258(18)98752-1

10.1016/S0945-053X(03)00014-3

10.1074/jbc.M209256200

10.1038/ng1116

10.1172/JCI200422715

10.1172/JCI200420641

10.1097/01.brs.0000152166.88174.1c

10.1016/S0092-8674(88)80033-3

10.1161/01.ATV.11.6.1660

10.1038/37284

10.1038/ng1511

10.1056/NEJM199904293401702

10.1097/01.hjh.0000182521.44440.c5

10.1161/01.CIR.103.6.789

10.1056/NEJM199405123301902

10.1002/tera.1420510603

10.1161/01.HYP.23.5.587

10.1007/s001099900028

10.1016/S0895-7061(99)00152-1

10.1152/ajprenal.00139.2003

10.1073/pnas.90.22.10759

10.1006/excr.1996.3398

10.1006/dbio.1996.0229

10.1136/heart.87.5.470

10.1016/j.yjmcc.2004.08.004

10.1038/sj.bjp.0704331

10.1161/hc37t1.094856

10.1161/01.CIR.0000024103.04821.86

10.1161/01.CIR.0000165133.84978.E2

P. J. Coucke et al. Nat. Genet. in press.

We thank K. Khan for expert technical assistance. Supported by the NIH (H.C.D. D.P.J. D.L.H. D.B.R. F.R.) the Smilow Center for Marfan Syndrome Research (H.C.D.) the National Marfan Foundation (H.C.D. D.P.J.) the Howard Hughes Medical Institute (H.C.D.) the Victor A. McKusick Endowment (H.C.D.) and the Dana and Albert “Cubby” Broccoli Center for Aortic Diseases (D.P.J.). All protocols for mouse treatment were approved by the Animal Care and Use Committee of the Johns Hopkins University School of Medicine.

Thông tin
Thông tin xuất bản

American Association for the Advancement of Science (AAAS)

Tập 312 Số 5770

117-121

Thông tin tác giả