Long-term effects of losartan on structure and function of the thoracic aorta in a mouse model of Marfan syndrome.
OBJECTIVE
During development of thoracic aortic aneurysms in a mouse model of Marfan syndrome, upregulation of matrix metalloproteinase (MMP)-2 and -9 was accompanied by compromised aortic constriction and endothelium-dependent relaxation. Losartan has been proposed for the prevention of thoracic aortic aneurysm. We hypothesized that losartan would suppress MMP-2/-9 activation and improve aortic vasomotor function in this model.


METHODS
A well-characterized mouse model of Marfan syndrome (Fbn1(C1039G/+)) was used. Starting at 6 weeks old, Marfan mice were untreated or given losartan (0.6 g.L(-1) in drinking water, n= 30). The littermate Fbn1(+/+) mice served as control. Thoracic aortas were studied at 3, 6 and 9 months by histology and by contractility assays in isolated segments in vitro.


RESULTS
Losartan improved elastic fibre organization and increased aortic breaking stress. Losartan reduced the activity and protein expression of MMP-2 and MMP-9 at all ages. Aortic constriction in response to membrane depolarization or phenylephrine was increased by losartan at 3 and 9 months by 100-200%. Active force of aortic smooth muscle was also increased at 6 and 9 months. Acetylcholine-induced endothelium-dependent relaxation was improved by 30% after 3 months of losartan treatment, but such improvement disappeared with longer duration of treatment, accompanied by reduced phosphorylation of endothelial nitric oxide (NO) synthase(Ser1177), Akt(Thr308) and Akt(Ser473), compared with the control.


CONCLUSIONS
Losartan improved the contractile function of aorta and reduced MMP activation. However, the endothelial NO pathway remained suppressed in the thoracic aorta during losartan treatment, which might limit its long-term benefits in Marfan syndrome.
Yang
H H Clarice
HH
Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Kim
Jong Moo
JM
Chum
Elliott
E
van Breemen
Cornelis
C
Chung
Ada W Y
AW
D000367:Age Factors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008382:Marfan Syndrome / Q000150:complications / Q000188:drug therapy*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D061965:Matrix Metalloproteinase Inhibitors; D009569:Nitric Oxide; D019808:Losartan