Androgens Accentuate TGF-β Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice.
Androgens Accentuate TGF-β Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice.
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DOI：
10.1161/jaha.119.015773
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发表时间：
2020-10-20
影响因子：
5.4
通讯作者：
Fischbein MP
中科院分区：
文献类型：
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作者：
Tashima Y;He H;Cui JZ;Pedroza AJ;Nakamura K;Yokoyama N;Iosef C;Burdon G;Koyano T;Yamaguchi A;Fischbein MP
与女性相比，男性马凡综合征患者发生主动脉事件和根部扩张的风险更高。雄激素在男性马凡综合征动脉瘤发展中所起的作用尚不清楚。我们假设雄激素增强转化生长因子β诱导的ERK(细胞外信号调节激酶)/Smad的激活，从而促进男性动脉瘤的进展。分别于6、8、12、16周龄时测量Fbn1 C1039G/+组和产仔野生型对照组的主动脉内径。Fbn1 C1039G/+雄性从6周龄到16周龄用雄激素受体阻滞剂氟他胺治疗或(2)赋形剂对照，然后安乐死。测定升主动脉根部和降主动脉组织中p-ERK1/2、p-Smad2和基质金属蛋白酶(MMPs)活性。利用Fbn1C1039G/+雄性和雌性升主动脉根部来源的平滑肌细胞，在体外检测双氢睾酮、氟他胺或转化生长因子β1处理后ERK/Smad的激活和基质金属蛋白酶-2的活性。Fbn1 C1039G/+男性有增加动脉瘤生长的趋势。在16周龄的升主动脉根部标本中，p-ERK1/2和p-Smad2表达升高。与ERK/Smad信号增强相对应，Fbn1 C1039G/+男性的MMP2活性更高。体外平滑肌细胞研究表明，双氢睾酮可增强转化生长因子β诱导的ERK/Smad激活和基质金属蛋白酶-2活性，而氟他胺可逆转这一作用。最后，在体内，氟他胺治疗通过减少p-ERK1/2和p-Smad2减少Fbn1 C1039G/+男性的动脉瘤生长。Fbn1 C1039G/+男性与女性相比，动脉瘤生长增强与p-ERK1/2和p-Smad2激活增强相关。从机制上讲，体外平滑肌细胞研究表明，双氢睾酮可增强转化生长因子β诱导的ERK/Smad激活。作为概念的生物学证据，氟他胺治疗减少了Fbn1 C1039G/+男性的动脉瘤生长和p-ERK1/2和p-Smad2信号转导。
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. 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. 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.