Deletion of AT1a (Angiotensin II Type 1a) Receptor or Inhibition of Angiotensinogen Synthesis Attenuates Thoracic Aortopathies in Fibrillin1C1041G/+ Mice

被引:15
作者
Chen, Jeff Z. [1 ,2 ,3 ]
Sawada, Hisashi [1 ,2 ,3 ]
Ye, Dien [1 ,2 ]
Katsumata, Yuriko [4 ,5 ]
Kukida, Masayoshi [1 ,2 ]
Ohno-Urabe, Satoko [1 ,2 ]
Moorleghen, Jessica J. [1 ,2 ]
Franklin, Michael K. [1 ,2 ]
Howatt, Deborah A. [1 ,2 ]
Sheppard, Mary B. [1 ,2 ,3 ,6 ,7 ]
Mullick, Adam E. [8 ]
Lu, Hong S. [1 ,2 ,3 ]
Daugherty, Alan [1 ,2 ,3 ]
机构
[1] Univ Kentucky, Saha Cardiovasc Res Ctr, Biomed Biol Sci Res Bldg,Room B243, Lexington, KY 40536 USA
[2] Univ Kentucky, Saha Aort Ctr JZC, Lexington, KY 40536 USA
[3] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA
[4] Univ Kentucky, Dept Biostat, Lexington, KY 40536 USA
[5] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
[6] Univ Kentucky, Dept Family & Community Med, Lexington, KY 40536 USA
[7] Univ Kentucky, Dept Surg, Lexington, KY 40536 USA
[8] Ionis Pharmaceut, Carlsbad, CA USA
基金
美国国家卫生研究院;
关键词
angiotensin II; angiotensinogen; aortic aneurysm; Marfan syndrome; renin-angiotensin system; AORTIC-ROOT DILATION; MOUSE MODEL; LOSARTAN; ANEURYSM; SYSTEMS;
D O I
10.1161/ATVBAHA.121.315715
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency (Fbn1(C1041G/+)). Approach and Results: Thoracic aortic aneurysm in Fbn1(C1041G/+) mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1(C1041G/+) females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1(C1041G/+) mice that were either +/+ or -/- for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1(C1041G/+) mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1(C1041G/+) mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathologies in the proximal thoracic aorta of male Fbn1(C1041G/+) mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1(C1041G/+) mice.
引用
收藏
页码:2538 / 2550
页数:13
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