Androgens Accentuate TGF-β Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice
Background Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced...
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Published in | Journal of the American Heart Association Vol. 9; no. 20; p. e015773 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
John Wiley and Sons Inc
20.10.2020
Wiley |
Subjects | |
Online Access | Get full text |
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Summary: | Background Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced Erk (extracellular-signal-regulated kinase)/Smad activation, contributing to aneurysm progression in males. Methods and Results Aortic diameters in
and littermate wild-type controls were measured at ages 6, 8, 12, and 16 weeks.
males were treated with (1) flutamide (androgen receptor blocker) or (2) vehicle control from age 6 to 16 weeks and then euthanized. p-Erk1/2, p-Smad2, and matrix metalloproteinase (MMP) activity were measured in ascending/aortic root and descending aorta specimens.
male and female ascending/aortic root-derived smooth muscle cells were utilized in vitro to measure Erk/Smad activation and MMP-2 activity following dihydrotestosterone, flutamide or transforming growth factor beta 1 treatment.
males have increased aneurysm growth. p-Erk1/2 and p-Smad2 were elevated in ascending/aortic root specimens at age 16 weeks. Corresponding with enhanced Erk/Smad signaling, MMP-2 activity was higher in
males. In vitro smooth muscle cell studies revealed that dihydrotestosterone potentiates transforming growth factor beta-induced Erk/Smad activation and MMP-2 activity, which is reversed by flutamide treatment. Finally, in vivo flutamide treatment reduced aneurysm growth via p-Erk1/2 and p-Smad2 reduction in
males. Conclusions
males have enhanced aneurysm growth compared with females associated with enhanced p-Erk1/2 and p-Smad2 activation. Mechanistically, in vitro smooth muscle cell studies suggested that dihydrotestosterone potentiates transforming growth factor beta induced Erk/Smad activation. As biological proof of concept, flutamide treatment attenuated aneurysm growth and p-Erk1/2 and p-Smad2 signaling in
males. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 For Sources of Funding and Disclosures, see page 15. Supplementary Material for this article is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.119.015773 See Editorial by Anderson et al. |
ISSN: | 2047-9980 2047-9980 |
DOI: | 10.1161/JAHA.119.015773 |