Androgens Accentuate TGF‐β Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice

Autor: Cristiana Iosef, Atsushi Yamaguchi, Michael P. Fischbein, Ken Nakamura, Albert J. Pedroza, Jason Z. Cui, Nobu Yokoyama, Tiffany K Koyano, Yasushi Tashima, Hao He, Grayson Burdon
Rok vydání: 2020
Předmět:
Male
MAPK/ERK pathway
Marfan syndrome
transforming growth factor‐β pathway aneurysm
Pathology
Translational Studies
Fibrillin-1
Male mice
Smad2 Protein
SMAD
030204 cardiovascular system & hematology
Marfan Syndrome
Mice
0302 clinical medicine
Transforming Growth Factor beta
Vascular Disease
Original Research
Mitogen-Activated Protein Kinase 1
0303 health sciences
Cardiovascular Surgery
Mitogen-Activated Protein Kinase 3
matrix metalloproteinases
Dihydrotestosterone
Organ Size
Editorial
gender differences
Androgens
Disease Progression
Matrix Metalloproteinase 2
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.medical_specialty
Cell signaling
Thoracic aortic aneurysm
03 medical and health sciences
Aneurysm
medicine
cell signaling
Animals
mitogen‐activated protein kinase
030304 developmental biology
Aortic Aneurysm
Thoracic
business.industry
Editorials
vascular biology
Androgen Antagonists
medicine.disease
Flutamide
aorta
Animal Models of Human Disease
business
Basic Science Research
Transforming growth factor
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: 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 Fbn1 C1039G/+ and littermate wild‐type controls were measured at ages 6, 8, 12, and 16 weeks. Fbn1 C1039G/+ 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. Fbn1 C1039G/+ 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. Fbn1 C1039G/+ 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 Fbn1 C1039G/+ 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 Fbn1 C1039G/+ males. Conclusions Fbn1 C1039G/+ 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 Fbn1 C1039G/+ males.
Databáze: OpenAIRE
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